RAPID PUBLICATION

Neuropsychiatric The Evolutionary Paradox and the Missing Heritability of Jenny van Dongen* and Dorret I. Boomsma Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands

Manuscript Received: 27 July 2012; Manuscript Accepted: 4 January 2013

Schizophrenia is one of the most detrimental common psychiat- ric disorders, occurring at a prevalence of approximately 1%, and How to Cite this Article: characterized by increased mortality and reduced reproduction, van Dongen J, Boomsma DI. 2013. The especially in men. The heritability has been estimated around Evolutionary Paradox and the Missing 70% and the genome-wide association meta-analyses conducted Heritability of Schizophrenia. by the Psychiatric Genomics Consortium have been successful at Am J Med Genet Part B 162B:122–136. identifying an increasing number of risk loci. Various theories have been proposed to explain why genetic variants that predis- pose to schizophrenia persist in the population, despite the fitness reduction in affected individuals, a question known as explain an important part of the variation in risk for many the evolutionary paradox. In this review, we consider - psychiatric disorders [Sullivan et al., 2000, 2003; McGuffin et al., ary perspectives of schizophrenia and of the empirical evidence 2003; Bulik et al., 2006; Lundstrom et al., 2012; Kan et al., 2013]. that may support these perspectives. Proposed evolutionary Estimates from ‘‘unrelated’’ subjects suggest that a significant part explanations include balancing selection, fitness trade-offs, fluc- of the variation in risk can be explained by genome-wide SNPs, with tuating environments, , -selection bal- 23% for schizophrenia [Lee et al., 2012], 38% for bipolar disorder ance and genomic conflicts. We address the expectations about [Lee et al., 2011], and 32% for major depressive disorder [Lubke the genetic architecture of schizophrenia that are predicted et al., 2012]. According to evolution theory the process of natural by different evolutionary scenarios and discuss the implications selection preserves genetic variants associated with survival and for genetic studies. Several potential sources of ‘‘missing’’ reproductive advantage (fitness), while genetic variants associated heritability, including gene–environment interactions, epige- with low fitness are eliminated from the gene pool [Darwin, 1859]. netic variation, and rare genetic variation are examined Given that genetic variants associated with reduced fitness are from an evolutionary perspective. A better understanding of under negative selection pressure, why is it that evolutionary history may provide valuable clues to the genetic has not eliminated genetic variants that predispose to psychiatric architecture of schizophrenia and other psychiatric disorders, disorders? This question has been addressed by many and is known which is highly relevant to genetic studies that aim to detect as the evolutionary paradox of psychiatric disorders. genetic risk variants. 2013 Wiley Periodicals, Inc. The paradox is most evident for disorders that have a high heritability and are associated with a large fitness reduction. Why Key words: schizophrenia; ; genetics; evolution; are harmful psychiatric disorders that are largely genetic in origin so missing heritability common? Schizophrenia is among the most heritable psychiatric disorders (heritability70% [Sullivan et al., 2003; Lichtenstein INTRODUCTION et al., 2009]) and also among the most severe. It is characterized The Evolutionary Paradox of Common Psychiatric by positive symptoms (i.e., , and racing thoughts), negative symptoms (i.e., poor social functioning, apa- Disorders thy, and lack of emotion), and cognitive symptoms (disorganized Common psychiatric disorders can be highly detrimental and many thoughts, concentration problems, memory problems, and diffi- are associated with a shorter lifespan [Hiroeh et al., 2001; Joukamaa et al., 2001; McGrath et al., 2008; Mouridsen et al., 2008]. Unlike common somatic disorders, common psychiatric disorders often Grant sponsor: European Research Council; Grant number: ERC-230374. *Correspondence to: emerge early in the reproductive age [Bebbington and Ramana, Jenny van Dongen, Department of Biological Psychology, VU University 1995; Andrade et al., 2003; Kessler et al., 2005; Rutter, 2005; Hoek, Amsterdam, Van der Boechorststraat 1, 1081BT, Amsterdam, The 2006; McGrath et al., 2008], conferring a substantial reproductive Netherlands. E-mail: [email protected] disadvantage [Baron et al., 1982; Haukka et al., 2003; King, 2003; Article first published online in Wiley Online Library Svensson et al., 2007; Williams et al., 2007]. Twin and adoption (wileyonlinelibrary.com): 25 January 2013 studies have indicated that genetic differences between individuals DOI 10.1002/ajmg.b.32135

2013 Wiley Periodicals, Inc. 122 VAN DONGEN AND BOOMSMA 123 culty with completing tasks) [Tamminga and Holcomb, 2005]. The identify susceptibility genes (‘‘the missing heritability’’ [Maher, onset is typically in early adulthood, with an earlier onset in men 2008]) may be closely linked. The difficulty in finding replicable than in women by on average 3–4 years [Hafner et al., 1993], and is genetic associations for psychiatric disorders that account for a usually followed by a lifelong course of social and professional substantial part of disease risk may be explained by a characteristic impairment. Individuals with schizophrenia show lower reproduc- genetic architecture that has been shaped by evolutionary history tive success (on average 30–80% relative to controls, with affected [Uher, 2009]. males showing a larger reduction in than In this review, we address the question how genetic risk for affected females [Del Giudice, 2010]) and suffer from increased schizophrenia may persist in the population. We consider evolu- mortality due to natural and unnatural causes ( in tionary perspectives on schizophrenia, evaluate the usefulness of particular) [Brown, 1997]. These disadvantages suggest that risk these theories in terms of explaining the persistence of heritable alleles for schizophrenia should be under negative selection. variation, and discuss various aspects of the genetic architecture of Yet, the disorder is surprisingly prevalent, affecting approximately schizophrenia that are predicted under different evolutionary 1% of individuals worldwide [McGrath et al., 2008]. A variety scenarios. Although schizophrenia is the central theme of most of evolutionary hypotheses has been proposed to explain the evolutionary theories, many of these theories may apply to a high prevalence of schizophrenia, despite the associated fitness broader concept of psychotic illness. Non-organic psychoses reduction and high heritability [Polimeni and Reiss, 2003; Brune,€ (i.e., psychoses in the absence of organic brain disorder) have 2004]. traditionally been divided into two diagnostic categories: schizo- phrenia and bipolar disorder [Tamminga and Holcomb, 2005]. A combination of symptoms that is intermediate of these two cate- The Evolutionary Paradox and the Missing gories may be classified as schizoaffective disorder, however, many clinical signs are shared across all psychotic disorders and it is Heritability: A Common Ground? unclear to which degree the different diagnostic categories are Although schizophrenia appears to be highly heritable, most of etiologically distinct. There is increasing support that there is at the genetic variants remain to be identified. Genetic linkage least partial overlap between genetic risk variants for schizophrenia studies have pointed at various loci, but these loci were rarely and bipolar disorder [International Schizophrenia Consortium, replicated across populations [Ng et al., 2009]. It was hypothesized 2009; Schizophrenia Psychiatric Genome-Wide Association Study that susceptibility to schizophrenia may be mediated by common Consortium, 2011] and such overlap may even extend to other genetic variants with small individual effects, a view known as the psychiatric disorders as well [Sullivan et al., 2012]. common disease-common variant (CDCV) hypothesis [Lander, 1996; Risch and Merikangas, 1996]. Genome-wide association studies (GWAS) have identified an increasing number of common Schizophrenia as an Evolutionary variants that appear to modify the risk of schizophrenia but these It has been suggested that psychiatric disorders should not be variants together explain only a small fraction of the total amount regarded as merely harmful conditions. Rather, these conditions, of genetic variation that is assumed to underlie the disorder associated traits, or underlying genes may provide certain advan- [International Schizophrenia Consortium, 2009; Wang et al., tages to affected individuals or their relatives, which may have been 2010; Schizophrenia Psychiatric Genome-Wide Association Study favored throughout evolutionary history [Kuttner et al., 1967; Consortium, 2011; Sullivan et al., 2012]. Recent findings from Kellet, 1973; Karlsson, 1977; Waddell, 1998]. Most of such advan- sequencing studies suggest that at least part of the genetic risk for tages were proposed for cognitive domains. For example, Kellet schizophrenia may be related to rare genetic variants that are [1973] suggested that personality traits associated with schizophre- difficult to detect in GWAS [McClellan and King, 2010; Tennessen nia such as inventiveness and the ability to tolerate low levels et al., 2012; Veltman and Brunner, 2012]. Evidence has emerged for of stimulation while remaining alert may offer good territorial a role of rare structural variants [International Schizophrenia instincts, which could have been advantageous to territorial ani- Consortium, 2008; Sullivan et al., 2012] and de novo single nucleo- mals. Although this theory might explain the persistence of such tide [Xu et al., 2012]. traits in ancestral times, modern allele frequencies depend mainly The genetic properties of populations are the result of natural on fitness in recent times. Irrespective of whether schizophrenia or selection in the past, together with mutation and random drift associated traits were indeed beneficial in the past, such theories do [Fisher, 1930]. A better understanding of the evolutionary history not clarify why risk alleles for schizophrenia exist today. of diseases may provide valuable insights into their genetic archi- Various other advantageous correlated phenotypes have been tecture and into suitable strategies to identity risk alleles. The proposed, which may also be of benefit in modern times, including hypothesis that common genetic variants influence the risk for social skills, creativity, musical skills, intelligence, and exceptional common psychiatric disorders relies upon important assumptions abilities. Associations of creativity with psychosis and about the evolutionary history of psychiatric disorders. Common are well-supported by empirical evidence; individuals with a high susceptibility alleles must be evolutionary ancient and cannot have score on schizotypy or with a history of psychosis on average score been subject to continuous strong negative selection pressure, since higher on measures of creativity and vice versa [O’Reilly et al., 2001; such variants should have reached fixation and no longer contribute Nettle and Clegg, 2006], and individuals with schizophrenia and to heritable variation in traits [Fisher, 1930]. The evolutionary bipolar disorder are overrepresented in creative and artistic occu- paradox of common psychiatric disorders and the difficulty to pations [Kyaga et al., 2011]. 124 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

Several authors have suggested a link between schizophrenia and for higher-order cognitive functions throughout evolutionary advantageous somatic characteristics. Among one of the earliest, history, despite the cost of predisposing to schizophrenia. Huxley et al. [1964] proposed that the disadvantage of schizophre- Schizophrenia could represent the extreme end of normal vari- nia susceptibility may be outweighed by advantages such as higher ation in cognitive skills. Farley [1976] proposed that schizophrenia resistance to infection, heat shock, and allergies. Several studies may be regarded as an outlier on the normal continuum of social have indeed demonstrated immune-related differences in schizo- behavior and as the toll that humans pay for the benefit of adaptive phrenia [Huxley et al., 1964; Schwarz et al., 1999; Muller et al., 2000; social skills genes. Crow referred to the link between schizophrenia, Strous and Shoenfeld, 2006], but it remains unclear to which degree language dysfunction, and cerebral flexibility to hypothesize that this characteristic is advantageous. While several studies have schizophrenia reflects the extreme end of variation underlying indicated that schizophrenia is associated with a lower risk of language capacity [Crow, 1995, 1997, 2000]. According to Crow, rheumatoid arthritis [Rubinstein, 1997; Oken and Schulzer, positive selection for cerebral flexibility during human evolution 1999; Gorwood et al., 2004], the incidence of various other auto- allowed for the emergence of language; however, a by-product of immune diseases, including thyrotoxicosis, celiac disease, acquired cerebral flexibility was the associated variation in psychological hemolytic anemia, interstitial cystitis, and Sjogren’s syndrome, has functioning, resulting in personality disorders and schizophrenia at been found to be elevated [Eaton et al., 2006]. the extremes. Dodgson and Gordon [2009] proposed that certain Another often cited potential benefit associated with schizo- types of hallucinations may be regarded as the evolutionary by- phrenia is lower susceptibility to cancer. Besides a possible protec- products of a cognitive system designed to detect threat. From an tive effect of antipsychotic drugs in cancer development [Carrillo evolutionary perspective, it might be better to mistakenly believe and Benitez, 1999], several characteristics of schizophrenia itself being threatened by an approaching predator than to fail to have been proposed to provide an inherent biological protection recognize it if one is really in danger. against cancer, including a protective effect of excess dopamine Randall emphasized the role of neural connections in the evolu- [Basu and Dasgupta, 2000], increased apoptosis [Catts and Catts, tion of human brain functions [Randall, 1983, 1998]. According 2000], and enhanced natural killer cell activity [Yovel et al., 2000]. to Randall, the random establishment of novel neural pathways Some studies have found a lower incidence of cancer among throughout development may produce advantageous supernormal schizophrenic patients compared to the general population connections or non-adaptive misconnections. This ‘‘biological trial [Mortensen, 1989; Cohen et al., 2002; Goldacre et al., 2005], also and error of connections’’ may give rise to a range of behavioral after correcting for risk factors such as age, race, gender, marital variants, including schizophrenia. Horrobin [1996, 1998, 1999] status, , and smoking [Cohen et al., 2002]. Yet, other focused on the biochemistry underlying such neural connections, studies have reported a similar or even higher incidence of several emphasizing the role of phospholipids biochemistry in the evolu- types of cancer in schizophrenia [Goldacre et al., 2005; Catts et al., tion of the human brain and in disorders such as schizophrenia. 2008] and mixed findings for the association between schizophre- According to this theory, a boost of neuronal membrane phospho- nia and cancer may be related to numerous confounders that have lipid metabolism resulting from the introduction of a larger not been accounted for in all studies [Bushe and Hodgson, 2010; amount of essential fatty acids in the early human’s diet triggered Hodgson et al., 2010], of which smoking could be most important the evolution of enhanced neuronal micro-connectivity. Though [de Leon and Diaz, 2005]. increased micro-connectivity may have allowed for the emergence Although schizophrenia may be associated with some positive of traits such as creative thinking, the authors propose that in- aspects, these aspects obviously do not outweigh the negative effects creased neuronal connectivity may also predispose to unwanted of this disorder to affected individuals. Neurocognitive studies have side-effects such as schizophrenia. Finally, schizophrenia has been highlighted that schizophrenic patients generally show marked proposed to result from delayed cerebral maturation, which may cognitive deficits [Heinrichs and Zakzanis, 1998]. Most important- represent a disadvantageous phenotype within the boundaries of ly, data on lifespan and reproduction of patients with schizophrenia normal variation in cerebral maturation [Saugstad, 1999]. show that any benefit experienced by these patients is apparently Although the disorder is approached from a different angle, not enough to prevent them from having a lower life expectancy and theoriesthat consider schizophrenia tobe a by-product of evolution fertility compared to the general population. Therefore, possible actually rely on a similar principle as theories in which schizophre- cognitive or somatic benefits to affected individuals cannot explain nia is considered as an evolutionary adaptation; both assume that the survival of genetic risk variants for schizophrenia. the disorder is somehow linked to beneficial characteristics. If schizophrenia has arisen as a by-product of evolution at the extreme Schizophrenia as a Trade-Off at the end of variation in ‘‘normal’’ traits, the question that still remains is why this extreme and maladaptive phenotype persists, or from a Extreme end of Variation genetic perspective; why the genetic variants responsible for this Several authors have suggested that schizophrenia may have arisen disorder are maintained in the population. as an unfavorable but inevitable (by-) product of human brain evolution. These theories have in common that schizophrenia is approached in the traditional perspective as a disorder, that is as a Balancing Selection phenotype that is purely disadvantageous to the affected individual. Most evolutionary perspectives on psychiatric disorders rely on According to this view, the high prevalence of the disorder is ‘‘balancing selection,’’ which refers to a situation where multiple explained by positive selection for genetic variants that allowed alleles may be maintained in the gene pool, if the genotypes are VAN DONGEN AND BOOMSMA 125 under different selection pressures, or if different selection pres- of ‘‘heterozygote advantage’’ is difficult to detect when it is sures act upon an individual allele under different circumstances. unknown which relatives are heterozygous for the responsible One example of balancing selection is presented by antagonistic genetic variant. pleiotropy, where the effect of a genetic variant is associated with Cliff-edged fitness refers to the increase in fitness associated with both advantageous and disadvantageous traits within the same increased expression of a trait up to a certain threshold, above which individual, making it selectively neutral. An example is the increased expression of the trait is associated with a sharp drop in P53 gene, which suppresses cancer, thereby increasing survival at fitness [Nesse, 2004]. A classic example of the cliff-edged fitness younger ages, but also suppresses stem cell proliferation, thereby model is provided by the tendency of some birds to lay fewer eggs contributing to the process of aging [Rodier et al., 2007]. The than they are capable of; birds that lay fewer eggs avoid the risk that hypothesis that schizophrenia risk alleles are potentially protective all offspring die under conditions of nutritional scarcity [Liou et al., to cancer is an example of antagonistic pleiotropy. 1993]. One theory that relies on the cliff-edged fitness model to Another example of balancing selection is presented by balanced explain the persistence of schizophrenia addresses the link between polymorphisms (heterozygote advantage). Thus, it has been pro- schizophrenia and synaptic pruning. Pruning, the selective elimi- posed that genetic variants that predispose to fitness-reducing nation of weak neuronal connections, is a normal developmental psychiatric disorders in homozygotes are maintained in the popu- process that occurs predominantly throughout childhood and lation because they are associated with a fitness-increasing trait in a adolescence. The elimination of little-used synapses improves large number of carriers (heterozygotes) [Huxley et al., 1964; mental efficiency; however, excessive reduction of synaptic con- Karlsson, 1977]. A classic example of a disease that is related to a nectivity (over-pruning) may result in spontaneous and autono- balanced polymorphism is sickle-cell anemia, a severe disease mous cerebral activity, causing hallucinations and other positive that presents in individuals who are recessively homozygous for symptoms [Hoffman and McGlashan, 1997]. The optimum level of the b-hemoglobin gene [Ashley-Koch et al., 2000]. The recessive pruning might lie just below the threshold above which psychosis allele is maintained in the gene pool because it confers resistance to may be induced. Therefore, evolutionary processes may select malaria in heterozygous carriers. Likewise, schizophrenia risk towards maximal neuritic pruning, despite the potential risk of alleles could be maintained in the population because they provide over-pruning. beneficial cognitive or somatic traits in unaffected carriers of these The cliff-edged fitness model has also been applied to explain alleles. Of note, a genome-wide scan to identify loci that have been the persistence of schizophrenia at the level of the underlying subject to balancing selection indicated that balanced polymor- genes. Thus, a small number of susceptibility alleles may be phisms are probably rare [Bubb et al., 2006]. beneficial to the individual, for example by providing good social Several authors have suggested that schizophrenia persists due skills and capacity [Nesse, 2004]. Too many to a benefit experienced by family members of affected individuals; susceptibility alleles, however, may be maladaptive and increase for example, schizophrenia may present in homozygous individu- the risk of schizophrenia. The cliff-edged fitness model also offers a als, while their heterozygous relatives experience superior social potential mechanism for the other theories stating that schizophre- skills [Kuttner et al., 1967], creativity [Karlsson, 1977; Post, 1994; nia has arisen as a by-product of evolution at the extreme-end of Waddell, 1998] or academic success [Jeste et al., 2000], thereby variation in some trait. Yet, the cliff-edged fitness model does not enjoying a selective advantage compared to the general population. actually solve the paradox, because it is not clear why natural Support for the link with creativity has been demonstrated for selection would maintain a number of harmful alleles in the healthy siblings of schizophrenia patients [Kyaga et al., 2011]. Yet, population that can lead to schizophrenia in a subset of individuals, similar cognitive deficits as seen in schizophrenia are often present, and has not rather selected a set of alleles that is beneficial to all although to a milder degree, in relatives without a diagnosis of individuals. schizophrenia [Sitskoorn et al., 2004; Snitz et al., 2006]. Both Another type of balancing selection is frequency-dependent affected individuals and their relatives perform worse than healthy selection, where the fitness of a phenotype depends on its frequency controls on a range of cognitive tasks, with the most pronounced relative to other phenotypes in the population. Positive frequency- deficits observed in verbal memory, executive functioning and dependent selection refers to the situation in which the fitness of a attention [Sitskoorn et al., 2004; Snitz et al., 2006]. With respect phenotype is increased as it becomes more common. For example, to cancer, conflicting findings have been found in unaffected bright warning (aposematic) coloration in a poisonous species is relatives of schizophrenic patients, with some studies reporting a associated with higher fitness when it is common, since predators lower incidence of cancer in relatives [Lichtermann et al., 2001; are more likely to avoid brightly colored individuals if most Catts et al., 2008] and others reporting a higher incidence [Dalton individuals are brightly colored [Endler, 1988]. Negative et al., 2004]. Some studies have reported increased fertility in frequency-dependent selection refers to the situation where the relatives of schizophrenic patients [Srinivasan and Padmavati, fitness of a phenotype increases as it becomes less common. For 1997; Avila et al., 2001], however, most studies have concluded example, female fruit flies prefer males with a rare phenotype, which that the fertility of relatives is not sufficient to outweigh the is called the ‘‘rare male advantage’’ [Som and Singh, 2005]. reproductive cost of schizophrenia [Bassett et al., 1996; Haukka et al., 2003; Svensson et al., 2007; MacCabe et al., 2009]. So far, there is thus no evidence for the hypothesis that the fitness cost Selfish Gene Theory and Group Advantages of schizophrenia is outweighed by an advantage experienced by In evolutionary biology, group selection theory refers to natural close relatives, although one might argue that a true instance selection favoring a trait that confers an advantage to the species as a 126 AMERICAN JOURNAL OF MEDICAL GENETICS PART B whole, regardless of the effect of the trait on the fitness of individuals Sexual Selection and the Evolution of Fitness within the group [Wilson, 1975]. Similarly, the selfish gene theory Indicators emphasizes that the preservation of a gene in the gene pool is determined by its ability to proliferate in the population, even if it Traits with a high heritability that appear puzzling from an predisposes the individual who carries it to self-sacrificing behavior evolutionary perspective have been explained by the theory of [Dawkins, 2006]. Group selection has for example been put forward sexual selection, which refers to the evolutionary selection of traits as an explanation for the (apparently) altruistic behavior of ‘‘helper associated with a reproductive advantage, rather than survival birds’’ observed in many bird species, which delay their own advantage and includes selection due to differences in intra-sexual reproductive efforts to help raising the offspring of close relatives competitive abilities (intra-sexual competition), and selection due [Emlen and Wrege, 1988]. Although such behavior decreases the to mate preferences of the choosier sex (intersexual selection). individual birds’ reproductive success and survival, it promotes the Intersexual selection may stimulate the evolution of traits such as survival of young relatives, thereby stimulating the propagation of attractive bright plumage in male birds, despite the survival the family’s genes. costs that are often associated with such traits [Emlen and Oring, The group selection approach has been adopted to explain the 1977]. For example, male peacocks have enormous tails that persistence of schizophrenia, by suggesting that the characteristics are energetically costly to grow, prevent the bird from flying, of some affected individuals may confer an advantage to the group. and make it an easy target for predators; however, the tails have For example, Price and Stevens [1998] proposed the group-splitting been favored by sexual selection because they attract females [Petrie hypothesis of schizophrenia, which states that schizotypal traits et al., 1991]. may reflect an ancient form of behavioral specialization for hunting Several theories have been proposed to explain why such traits and gathering tribes. This hypothesis relies on the assumption that attract the opposite sex. The good-genes theory states that individ- in ancient times, proliferating tribal communities had to split from uals of the choosier sex prefer features of mates that advertise time to time to maintain optimum numbers. According to Price genetic fitness [Houle and Kondrashov, 2002]. The fitness indicator and Stevens, schizotypal traits in certain prominent individuals theory is slightly broader, and states that mate preference traits may have been advantageous to ensure survival of an offshoot reveal to potential mates an individual’s underlying genetic quality group. To illustrate their hypothesis, they suggested that schizo- (e.g., mutational load) and condition (e.g., nutritional status and typal traits are often found in charismatic leaders, who use parasite load) [Kokko et al., 2003]. Selection pressures favor ‘‘delusions, paranoia, and religious themes to fraction disaffected individuals who prefer mates with high-quality fitness indicators, groups and to seed new .’’ This type of leadership could be since such mates are more likely to successfully produce offspring regarded as an altruistic behavior that is maintained by group with high fitness. Fitness indicators may comprise behavioral selection. features such as the courtship songs of birds [Nowicki et al., A second group selection theory of schizophrenia has highlight- 2000]. Theoretically, the most informative fitness indicators are ed the link between schizophrenia and shamanism [Polimeni and to a large degree influenced by genetic variation (to allow for Reiss, 2002]. Schizophrenia and associated traits may be advanta- advertising genetic fitness) and are at the same time highly sensitive geous for shamans to perform religious rituals. Since religious to the environment (to allow for advertising overall fitness). rituals and shamans are universally observed across all cultures, Visible human body traits may have evolved as fitness indicators, this activity may have a genetic basis, and may be relevant to the including male facial structure, muscularity, and height [Perrett survival of humankind. This theory was proposed to be supported et al., 1994], and female breasts [Barber, 1995]. Shaner et al. [2004] by the numerous reports of religious-based delusions in psychotic proposed that human mental and behavioral characteristics individuals [Maslowski et al., 1998]. may also have evolved as fitness indicator. This fitness indicator A third group selection hypothesis of schizophrenia relies may involve verbal courtship behaviors (e.g., ‘‘attracting on the mechanism of frequency-dependent balancing selection mates by telling funny stories with creativity, social sensitivity, [Allen and Sarich, 1988]). This hypothesis states that individuals and emotional expressiveness’’). In individuals with good genes and with some genetic susceptibility to schizophrenia may have a a favorable prenatal and postnatal environment, neurodevelop- survival advantage by possessing a greater sense of individuality, mental processes influencing these mental characteristics result and the ability to ‘‘resist shared biases and misconceptions of in successful courtship behavior. A poor genetic background the group.’’ The authors of this hypothesis propose that the (due to harmful alleles) or environmental background, however, integrity of a group can sustain some betrayal if there are leads to unsuccessful courtship behavior that repels potential mates. some non-conformists; however, too many would hinder a According to Shaner et al. schizophrenia represents the unattractive harmonious society. It was also suggested that this theory may and dysfunctional extreme of a highly variable trait shaped explain why schizophrenia is more prevalent in modern industrial by sexual selection. A computational model developed by Del societies [McGrath et al., 2008]. Complex societies are more Giudice [2010] demonstrates that the sexual selection model is tolerant to individuals with a greater sense of individuality and compatible with reduced fertility in families of schizophrenic may benefit from a modest number of individuals with such patients. Yet, the existence of traits that advertise genetic fitness characteristics. Yet, as for the other group selection theories, it only makes sense as long as harmful genetic variants (‘‘bad genes’’) is difficult if not impossible to assess whether group selection are present in the population, and the question is why such variants mechanisms contribute to the persistence of risk alleles for (still) exist if they produce an ‘‘unattractive’’ phenotype with lower schizophrenia. fitness. VAN DONGEN AND BOOMSMA 127

Recessive Alleles and Epistasis evolutionary forces acting on a continuous lineage from one-celled One factor that is of major importance for the outcome of natural organism with no fresh start. Therefore, most aspects of the human selection on a phenotype is the mode of action of the underlying body depend on aspects that evolved earlier in a way that sub- genes, for example whether causal alleles act in an additive, domi- optimal characteristics may not be set straight. nant, or recessive manner [Fisher, 1930]. If a maladaptive pheno- An example of a suboptimal morphological characteristic that type results from a dominant allele or additive gene effect at a locus, has been suggested to reflect path dependence in evolutionary fitness will be decreased in all carriers of the risk allele and the risk history is the recurrent (inferior) laryngeal nerve, which is a branch allele will go extinct while the other allele will reach fixation. On the of the vagus nerve (tenth cranial nerve) that supplies motor other hand, if a maladaptive phenotype results from the action of function and sensation to the larynx [Dawkins, 2009]. The nerve a recessive allele, selection will only act on individuals that are takes a remarkable detour to reach its target: it descends from the homozygous for this allele. In heterozygous individuals, the mal- brain into the thorax, loops around the aorta, and travels back to adaptive phenotype will not come to expression and the recessive innervate the laryngeal muscles in the neck. This pathway does not allele will be ‘‘invisible’’ to natural selection. The persistence of risk seem to make sense but is thought to reflect a design that originates alleles for schizophrenia may therefore in part be explained by the from an ancient ancestor in which major blood vessels were located action of recessive alleles that are difficult to eliminate by natural much closer to the target of this nerve. Thus, the recurrent nerve is selection. Natural selection similarly acts more slowly on maladap- also present in fish, in which it is the fourth branch of the vagus tive traits that result from the interaction of multiple loci (epistasis), nerve innervating one of the posterior gills. The example illustrates in which case the fitness of individuals is determined by the that once selection has shaped a trait into a certain direction over combination of alleles at each locus. For maladaptive traits that evolutionary time, evolution cannot go back in time to reverse it if arise from epistatic interactions among multiple loci, a ‘‘risk allele’’ the trait becomes suboptimal later in evolutionary time. The is only associated with reduced fitness in individuals with the evolution of the human brain may also have been limited by specific combination of alleles, while the same allele can be harmless such constraints. in individuals with other combinations. The triune brain concept is a model in which the human brain Negative selection pressures on recessive alleles can explain the contains the evolutionary remnants of three ancestral brains: the well-described phenomenon of inbreeding , where a reptilian brain (upper brain stem), the paleomammalian brain drop of fitness is observed in the offspring of related parents, (limbic area), and the neomammalian brain (cortical region) because inbreeding increases the chance that offspring are homo- [MacLean, 1977, 1985]. According to this model, each successive zygous for deleterious recessive alleles [Wright, 1977; Keller et al., brain area that was introduced incorporates and modifies previous 2011]. Schizophrenia is more prevalent in populations with higher functions. Millar [1987] proposed that the introduction of each levels of inbreeding [Bittles and Black, 2010; Mansour et al., 2010], successive brain feature may have come with difficulties connecting which supports the role of rare recessive variants, and suggests that pre-existing and novel parts, and hypothesized that schizophrenia these variants may have been subject to negative selection, although may reflect a failure of integration between different parts, in other factors, for example, demographic, social, and economic ones particular between the limbus and cortex, an error that may may also influence such outcomes. Additional support for the have resulted from a suboptimal brain design due to evolutionary role of recessive alleles in schizophrenia comes from a study of constraints. However, the benefits of having a more complex brain runs of homozygosity (ROH, long stretches of homozygous that allowed for novel functions such as language may have out- polymorphisms), which showed that ROH were more common weighed the disadvantage that the design is sensitive to errors. But in schizophrenia patients and found that several specific ROH were how can path dependence in the history of brain evolution explain present in schizophrenia patients that were very rare in healthy the survival of heritable risk factors for schizophrenia? Why do subjects [Lencz et al., 2007]. errors in brain development only lead to problems in some indi- viduals, and if there is a genetic cause for this why is it not wiped out by selection? If a developmental outcome (brain function) is determined by Fitness Trade-Offs the interaction of multiple areas and the development of each area is From an evolutionary perspective, all phenotypes can be regarded guided by its own genetic information, this suggests that the effect of as compromises. Evolution does not strive for perfection. Rather, it an allele on an individual’s outcome may depend on the presence of drives traits towards an optimum level where fitness and trade-offs (many) other alleles, which implies epistasis. Yet, if there is even a are balanced. For example, ‘‘our immune systems could be more very small difference in the fitness between different combinations aggressive, but only at the cost of damaging our own tissue’’ [Nesse, of alleles, natural selection generally favors the most fit set of alleles, 2006]. Perhaps schizophrenia could have been eliminated by natu- thus to maintain genetic variation there must be additional factors ral selection, but at the expense of loosing valuable cognitive traits. that play a role. Keller and Miller [2006] illustrated the biological The capacity of natural selection to optimize traits is bounded by network of mechanisms that ultimately produce behavior by using a some important constraints [Nesse, 2006]. Firstly, natural selection watershed analogy: a huge number of ‘‘upstream’’ biological pro- represents a stochastic process; certain mutations that could be cesses (e.g., neuron proliferation, dendritic pruning, etc.) eventu- of benefit to a species may never occur, while harmful mutations ally flows into all sorts of ‘‘downstream’’ processes (e.g., language, can go to fixation by mere chance. Another important constraint learning capacity etc.). One mutation in an upstream process can is path dependence, which refers to humans being the result of affect many downstream processes, and one downstream process 128 AMERICAN JOURNAL OF MEDICAL GENETICS PART B can be influenced by mutations in many different upstream pro- toxins, and harmful mutations introduce random effects and cesses. Keller and Miller [2006] suggested that the watershed model imprecision in developmental pathways [Markow, 1992, 1995; predicts that downstream fitness-related traits such as psychiatric Yeo et al., 1999]. An example of a feature that is thought to reflect disorders have a high heritability because they result from the developmental instability is fluctuating asymmetry, which is integration of so many processes and are therefore highly polygenic. indexed, for example, by differential ear length. Though the left Support for the watershed model comes from the finding that most and right ears are on average of equal size in the population, the ears rare structural variants that contribute to the risk of schizophrenia of an individual may differ slightly, and this could reflect ‘‘noise’’ in also increase risk of , developmental delay, intellectual development. Fluctuating asymmetry may also affect developmen- disability, epilepsy, somatic dysmorphism, and extremes of body tal processes in the brain; an example that is thought to illustrate this mass and head size [Sullivan et al., 2012]. Of interest to the is hand preference. Schizophrenic patients show greater dermato- developmental perspective, it was found that a large proportion glyphic fluctuating asymmetry and more often show atypical of de novo mutations in schizophrenic patients were present within (mixed) handedness [Mellor, 1992; Reilly et al., 2001]. Natural genes with a higher expression in the early and mid-stage fetal selection should favor individuals that are capable of buffering period [Xu et al., 2012]. perturbations of developmental pathways, but it has been suggested that an important part of the genetic variation in developmental Mutation Selection Balance instability may consist of genetic variation in the ability to resist pathogens [Yeo et al., 1999]. Such variation can be maintained Harmful mutations are removed from the gene pool at a rate in populations by the process of host-parasite co-evolution proportional to their effect on fitness. Yet, novel mutations occur [Woolhouse et al., 2002]. Of interest to this theory, the strongest all the time. The polygenic mutation-selection balance hypothesis genetic association for schizophrenia that has thus far emerged states that the persistence of schizophrenia and other heritable from GWAS is in the major histocompatability complex (MHC) common mental disorders may be ascribed to the continuous region [Sullivan et al., 2012]. occurrence of new mutations [Pritchard, 2001; Keller and Miller, Rather than being a pathological maladaptation to developmen- 2006]. These mutations are harmful and under negative selection tal insults, schizophrenia has also been suggested to represent pressure; however, the elimination of fitness reducing mutations an adaptively programmed phenotype that is induced by environ- may be balanced by the continuous arrival of new mutations. The mental adversity. Many organisms express strikingly variable mor- À8 rate of de novo mutations is low (around 1.2 Â 10 per nucleotide phologies in response to variable environmental conditions per generation [Kong et al., 2012]), but mental may encountered during development, many of which are thought be influenced by many mutations, since the brain depends on to represent alternative survival or reproductive strategies. The the functioning of a large number of genes and their regulatory phenotypic plasticity hypothesis states that exposure to adverse sequences. It has been estimated that human individuals carry on environmental cues during early development may induce alter- average 500 mutations with fitness-reducing effects on brain func- ations in the expression of genes, resulting in a phenotype that is tion that have not yet been removed by selection [Keller and Miller, better suited for a stressful or deprived environment [Feinberg, 2006]. 2007]. According to Reser [2007], some of the core characteristics of Polygenic mutation selection balance appears to be the most schizophrenia that predict social and vocational disabilities in likely evolutionary explanation for the maintenance of genetic modern times, such as the inability to calm instinctual drives, variation for psychiatric disorders with a remarkable reproductive ignore arousing stimuli, and inhibit transient desires may represent disadvantage, such as schizophrenia [Keller and Miller, 2006; a ‘‘defensive, vigilance-based behavioral strategy that alerts the McClellan et al., 2007; Ng et al., 2009]. The hypothesis may be organism to salient, potentially informative stimuli and permits supported by the paternal age effect that has been observed for it to be more impulsive and vigilant.’’ Thus, schizophrenia may be schizophrenia, that is, the risk of schizophrenia in offspring related to physiological and behavioral characteristics that created increases with increasing paternal age [Malaspina et al., 2002], a fitness advantage in the ancestral environment under conditions and sequencing studies have shown that the age of the father at of nutritional scarcity and severe environmental stress. The link conception is associated with the number of de novo mutations in between schizophrenia and environmental adversity may be sup- offspring [Kong et al., 2012; Xu et al., 2012]. The number of de novo ported by several observations. Brain areas in the hippocampus mutations was shown to increase with two extra mutations per and frontal lobes that become hypometabolic in schizophrenia year under a linear model, or doubled every 16.5 years under an [Tamminga et al., 1992; Andreasen et al., 1994; Carter et al., 1998] exponential model [Kong et al., 2012]. have also been demonstrated to become adaptively hypometabolic in response to starvation, stress and variations in ecological rigor in Developmental Instability and Phenotypic other mammals and birds [Jacobs, 1996; Planel et al., 2001]. Furthermore, schizophrenia has been linked to exposure to stress Plasticity during development. Thus, maternal malnutrition [Susser et al., Schizophrenia has been proposed to represent a failure to express 1996], maternal stress [Khashan et al., 2008], multiparity [Hultman precisely an ‘‘intended’’ developmental design due to perturbations et al., 1999], short birth interval [Smits et al., 2004], and stressful caused by deleterious environmental influences and mutations. The postnatal events [Norman and Malla, 1993] are all risk factors for developmental instability model states that during development, schizophrenia, and certain neurophysiological characteristics of environmental and genetic perturbations, including pathogens, schizophrenia can be induced in animals through exposure to VAN DONGEN AND BOOMSMA 129 prenatal and postnatal stressors [Schneider et al., 1999; McClure compatible with the implicated role of epigenetic mechanisms, as et al., 2004]. increasing paternal is associated with increased risk of epigenetic abnormalities [Perrin et al., 2007]. The Mismatch Hypothesis While schizophrenia may present a fitness cost in modern societies, Sexual and Genomic Conflicts at Imprinted Genes this might not have been the case throughout the entire evolution- Sexual conflict arises when the two sexes of a species have con- ary history of humankind [Gluckman and Hanson, 2006]. This flicting optimal reproductive strategies, leading to an hypothesis is supported by the fact that the prevalence of arms race between males and females [Chapman, 2009]. In many schizophrenia seems to be quite variable across different locations species, reproduction is characterized by differential investment of [McGrath et al., 2008], with the highest rates generally found in the sexes in their offspring. In mammals, the mother is predomi- urban areas [Kirkbride et al., 2006]. The mismatch hypothesis has nantly responsible for providing resources to offspring pre- and been translated in various ways. Firstly, genetic variants that perinatally. As a result, the fitness of maternally derived alleles predispose to schizophrenia in modern times may have been favors smaller demand on maternal resources, anticipating on the adaptive in ancient environments (ancestral adaptation [Di Rienzo survival of future offspring, than paternally derived alleles, which and Hudson, 2005]). Secondly, schizophrenia may have been are associated with high fitness if offspring exploit as much resour- selectively neutral throughout most of human evolutionary history ces from the mother as possible. It is thought that the level of (ancestral neutrality hypothesis [Tooby and Cosmides, 1990]). expression that maximizes the fitness of an allele depends on Thirdly, schizophrenia may persist due to variable selective pres- whether the allele was present in a male or a female in the previous sures as a result of fluctuating environmental conditions [Feinberg generation. and Irizarry, 2010]. At imprinted genes, the expression pattern of an allele depends on its parent of origin [Reik and Walter, 2001]. Typically, one allele Epigenetic Variation as an Evolutionary is expressed, while the other is transcriptionally silent. The kinship theory of imprinting states that the evolution of imprinted gene Adaptation to Fluctuating Environments expression originates from the conflict of interests between mater- How can the persistence of variation in genetic risk be explained if nally and paternally derived alleles at a locus. Paternally derived the outcome depends on environmental factors, as predicted by the alleles favor higher growth rates of offspring and greater demand phenotypic plasticity model?Feinbergand Irizarry [2010] proposed on maternal resources than maternally derived alleles. Therefore, a framework that describes how genotypes may influence fitness by growth promoting loci are often maternally silenced through regulating the variability of a trait in a population, rather than by imprinting, whereas loci that suppress growth are often paternally influencing the average level of the trait. Thus, the authorssuggested silenced [Haig, 2004]. that certain loci regulate the plasticity of development of individuals A well-studied example of an imprinted gene is the IGF2 gene, by influencing stochastic variation in gene expression. The sug- which encodes a growth promoting factor that is only expressed gested loci are CpG islands, the density of which may vary between from the paternal allele. In humans, imprinting defects that activate individuals due to genetic polymorphisms, presenting an inherited the silenced maternal allele result in Beckwith–Wiedemann syn- basis of variably methylated regions (VMRs). Epigenetic variation drome, an over-growth syndrome characterized by a 50% increase at VMRs influence variation in the expression of nearby genes in birth weight [Weksberg et al., 1993]. Conversely, imprinting [Jones and Takai, 2001], which can give rise to large stochastic defects that cause the silencing of both alleles give rise to an under- variability in phenotypes under a given genetic background. growth syndrome called Silver–Russell syndrome [Gicquel et al., This type of genetically inherited stochastic variation may pro- 2005]. Imprinting is thought to be particularly important for genes vide a powerful mechanism for evolutionary adaptation to variable expressed in the placenta, but is also frequently observed for genes environments. Using simulations, the authors demonstrate that with a role in brain development [Wilkinson et al., 2007; Gregg under fluctuating environmental conditions, a genetically inherited et al., 2010]. Thus, the genetic conflict over maternal investment propensity to phenotypic variability increases fitness of a popula- may also affect behavior, cognition and personality of offspring tion despite increasing disease susceptibility. In other words, the [Badcock and Crespi, 2008]. fitness of individuals may be determined in part bythe abilityto vary Badcock and Crespi suggest that the ‘‘genetic war’’ at imprinted around a certain phenotypic level (or disease risk), rather than by genes for brain development may give rise to mental disorders if the phenotypic level itself, as this may be the best strategy for the expression is pushed too far towards the benefit of one of the population when environmental factors are not constant. The parental alleles. Paternally biased expression of genes involved in model of genetically inherited stochastic epigenetic variation pro- brain development may give rise to a self-oriented child that is vides a molecular mechanism for the phenotypic plasticity para- highly demanding to its mother, extreme cases being recognized as digm, and may explain how the persistence of disadvantageous autism. In line with this theory, Beckwith–Wiedemann patients traits such as schizophrenia may be stimulated by the pressures of have an increased risk of autism [Kent et al., 2008], and individuals variable environments and at the same time have a heritable basis. with autism tend to show increased IGF2 expression [Mills et al., Of interest, several studies have reported epigenetic alterations in 2007]. Badcock and Crespi hypothesized that small deviations in schizophrenia [Iwamoto et al., 2005; Huang and Akbarian, 2007; imprinted gene expression towards a maternal bias may lead to Veldic et al., 2007; Tochigi et al., 2008]. The paternal age effect is also offspring that are energetically ‘‘cheaper’’ and easier behaviorally to 130 AMERICAN JOURNAL OF MEDICAL GENETICS PART B mothers, that is, more placid, less demanding and better capable of the genetic architecture of schizophrenia, which is relevant to interpreting and understanding the mental states of others. Large genetic studies that aim to identify genetic variants. maternally biased deviations may lead to psychosis. The authors The polygenic mutation-selection balance model offers an ex- suggest that several characteristics of autism and psychosis may be planation for how fitness-reducing genetic variation is maintained regarded as opposites in the context of parental demand, that is, in the population; harmful mutations are under negative selection autistic spectrum conditions are characterized by deficits in theory- but variation persists because the removal of alleles is balanced by of-mind skills, or ‘‘hypo-mentalism,’’ whereas psychotic spectrum the occurrence of new mutations in the population. Of interest, a conditions involve the opposite: ‘‘hyper-mentalism.’’ For example, study of the rate of de novo occurrence and overall frequency of ten people with autism are characterized by a defective detection of gaze large and rare recurrent DNA copy number variants (CNVs) that and inability to appreciate what goes on in groups, while individuals have been associated with schizophrenia and other neurodevelop- with schizophrenia may experience paranoid delusions of conspir- mental disorders indicated that all of these variants are under strong acies and being watched by others. negative selection [Rees et al., 2011]. The highest selection coef- Some empirical support for the theory of Badcock and Crespi is ficients were observed for the rarest CNVs, and given the observed provided by findings in a region that contains several imprinted selection pressures, de novo CNVs at these loci appear to persist in genes on chromosome 15. Paternally biased expression of this the population for only a few generations. To date, various studies region causes Angelman syndrome, a disorder that is highly co- have identified rare SNPs and structural variants that are associated morbid with autism, while maternally biased expression of the same with the risk of schizophrenia [International Schizophrenia region causes Prader–Willi syndrome, a condition that is often Consortium, 2008; Sullivan et al., 2012; Xu et al., 2012], and the accompanied by psychotic symptoms [Nicholls et al., 1998]. Several polygenic mutation-selection model predicts that many more rare genes have been found to contribute to risk of autism, schizophre- genetic variants are likely to contribute to the risk of schizophrenia nia, and bipolar disorder at the same time [Carroll and Owen, in the population. 2009], but it remains to be established whether these genes are Theoriesthat proposethat schizophrenia is in some way linkedto imprinted and whether the expression of the genes may differ across adaptive traits, such as social skills, creativity, or pathogen resis- disorders. To conclude, fluctuations in imprinted gene expression tance suggest that genetic risk variants persist through balancing that result from the ongoing conflict between reproductive strate- selection; alleles that confer risk to schizophrenia are maintained in gies of males and females may contribute to the persistence of fitness the population because they are of benefit to unaffected individuals. decreasing conditions such as schizophrenia. Because epigenetic These theories imply that genetic risk variants are common. Other mechanisms that regulate imprinting can be influenced by genetic mechanisms that may account for the maintenance of common variation [Feinberg and Irizarry, 2010], this theory is compatible genetic variants that contribute to disease risk include genomic and with the persistence of heritable variation. sexual conflicts, and the maintenance of genetic variation at CpG Wilkins addressed the situation of imprinted genes with pleio- sites as an adaptation to fluctuating environmental pressures. It is tropic effects, and suggested that natural selection can systemati- often thought that environmental approaches cannot explain the cally cause a loss of fitness and fixation of maladaptive phenotypes paradox of psychiatric disorders, because environmental explana- due to genomic conflicts [Wilkins, 2010]. At imprinted loci, selec- tions do not seem to be compatible with the high heritability. tion is driven exclusively by the fitness of the active allele. When a However, we have discussed how environmental pressures may in phenotype is influenced by multiple oppositely imprinted loci, an fact contribute to the maintenance of heritable variation in areas interlocus conflict arises, because any given level of the phenotype that regulate gene expression. will be associated with differential fitness effects for the underlying An important difference exists between perspectives that assume maternally versus paternally expressed loci. Using a mathematical that the fitness cost associated with schizophrenia is balanced by model to describe a pair of antagonistic imprinted genes (one increased fitness in relatives, and those that see schizophrenia as a paternally expressed and one maternally expressed) with pleiotro- maladaptive by-product of evolution, or fitness trade-off that pic phenotypic effects (i.e., both genes influence multiple pheno- persists at the benefit of humankind. Distinct mechanisms have typic aspects), it was demonstrated that the genomic conflicts that been proposed to account for these alternative scenarios, which arise can cause natural selection to drive phenotypes away from make different predictions about the genetic architecture of schizo- their optimum values, resulting in a maladaptive, but selectively phrenia. The ‘‘heterozygote advantage’’ model proposed to account favored, evolutionary trajectory. According to this theory, mental for increased fitness in relatives may be the most convenient disorders that occur at high frequencies despite reducing individual evolutionary scenario for genetic association studies (e.g., GWA fitness, such as schizophrenia, may be related to pleiotropic effects studies), as cases and controls are expected to differ at common of imprinted gene expression in the brain. polymorphisms (with adaptive heterozygote genotypes being over- represented among controls). Yet, current data on fitness of rela- tives does not appear to support this model, nor does the fact that CONCLUSIONS genetic variants with large effects on the risk of schizophrenia have not emerged from GWAS. We have presented a variety of evolutionary perspectives of schizo- Perspectives in which schizophrenia is considered to represent a phrenia and addressed how they might explain the persistence of maladaptive by-product of genetic variants required for complex genetic risk variants for schizophrenia in the population. The cognitive functions suggest that every individual carries some different evolutionary scenarios make different assumptions about genetic susceptibility to schizophrenia, and whether individuals VAN DONGEN AND BOOMSMA 131 are affected may depend on the number of susceptibility alleles they has shaped the brain, and that it is not strange from an evolutionary carry (cliff-edged fitness), or on the combination of alleles across perspective that this design can be sensitive to errors (e.g., path multiple loci (epistasis). The cliff-edged fitness paradigm predicts dependence, fitness trade-offs and developmental instability). Sev- that inter-individual variation in cognitive characteristics is not eral theories imply that environmental exposures are important, so much determined by the particular genotype at each locus. including the mismatch hypothesis, the phenotypic plasticity hy- Although susceptibility alleles generally give rise to favorable cog- pothesis, the fitness indicator theory and the theory of stochastic nitive traits, too many alleles result in schizophrenia. Since many epigenetic variation. These perspectives are closely linked to each combinations of susceptibility alleles may predispose to schizo- other, and they all predict that gene–environment interactions and phrenia as long as the total number of alleles is large enough, this epigenetic variation contribute to the etiology of schizophrenia. scenario is a difficult one for case–control association studies or Genetic variants that predispose to schizophrenia may confer risk to linkage studies. The scenario would in fact be in line with the the condition by increasing environmental sensitivity [van Os et al., variable linkage results that have been reported, since affected 2010] and may therefore be associated with the amount of variation individuals might be distinguished from non-affected relatives in the phenotype rather than with a specific mean level. Detection of by the additional presence of any copy from the total pool of such genetic variants will require novel methodologies and statisti- susceptibility alleles. Thus, although the genetic architecture of cal approaches. This evolutionary scenario is also in line with schizophrenia under the cliff-edged fitness paradigm could be in variable linkage and association results across different popula- line with the CDCV hypothesis, it may explain the limited success of tions, since different populations may show different levels of the gene finding studies, since the success of detecting susceptibility relevant environmental exposures. Part of the heritability of schizo- alleles under this scenario critically depends on the study design. phrenia may reflect genetic variation that contributes to the expo- Epistasis likewise implies that single-SNP tests as usually conducted sure to certain environments (gene–environment correlation), as in GWAS are not the optimal strategy to identify common risk several ‘‘environmental risk factors’’ of schizophrenia, for example variants for schizophrenia, although main effects are expected to smoking [Li et al., 2003] and cannabis use [Agrawal and Lynskey, exist for individual alleles, which should be identified when sample 2006], are known to be to heritable to some extent. sizes are large enough. Yet, as the overall effects of these alleles on An important point of critique that has been raised in response to fitness are expected to be very small from an evolutionary perspec- evolutionary approaches of schizophrenia is that most take for tive (otherwise they would have been eliminated by natural granted that schizophrenia represents a trait that is ‘‘visible’’ to selection), the individual effects of these alleles when compared natural selection. Thus, one of the core assumptions of evolutionary between cases and controls are likewise expected to be very small. and biomedical psychiatry in general is that schizophre- The hypothesis that genetic variants that predispose to schizo- nia and other mental disorders are natural kinds, that is, bounded phrenia may have been favored by natural selection is supported by entities with discrete biological causes [Adriaens, 2008]. Given the some empirical evidence. Several genes that have been linked to phenotypic heterogeneity of schizophrenia and the assumed un- schizophrenia appear to show signs of positive selection in the derlying genetic heterogeneity [Fanous and Kendler, 2005; Fanous human lineage, including disrupted in schizophrenia 1 (DISC1), and Kendler, 2008], the ‘‘construct’’ schizophrenia may not have a dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 discrete biological cause, but may rather represent an umbrella (NRG1), each of which is thought to play an important role in concept that covers a heterogeneous group of disorders. The brain development [Crespi et al., 2007]. Several genes related to heterogeneity hypothesis predicts that genetic studies of schizo- energy metabolism that have been implicated in the pathophysiol- phrenia may benefit from focusing on underlying mechanisms with ogy of schizophrenia also appear to have undergone rapid changes a more homogeneous biological foundation, rather than disease in the human lineage [Khaitovich et al., 2008]. It thus seems that at status (affected vs. unaffected) as determined by clinical guidelines. least some of the variants associated with schizophrenia may have Several authors have proposed a unitary model of psychosis [van been favored by natural selection. Os, 2003; Craddock and Owen, 2007; Nuevo et al., 2012] and this Perhaps the strongest evidence for the role of common genetic hypothesis should also be kept in mind when considering the variants for schizophrenia comes from the estimate that 23% of the evolutionary history of schizophrenia. In fact, both from evolu- variation in disease risk can be explained by all genome-wide SNPs tionary and genetic perspective, diagnostic categories of psychiatric from SNP arrays together [Lee et al., 2012]. Though some of this disorders can be arbitrary, and it seems likely that many genetic signal may come from rare genetic variants, strong evidence for the variants may contribute to the risk of multiple disorders at the same importance of common genetic variants is implicated. Common time. variants can only persist in the population if they are maintained by An important general issue in evolutionary biology is the debate some sort of balancing mechanism (e.g., antagonistic pleiotropy, over the level of selection, which refers to the question which level of fluctuating environments, or genomic conflicts), or if the individ- the biological hierarchy is touched by natural selection. Does ual effect of risk variants on fitness is so small that relatively high natural selection act on organisms, genes, groups, populations, allele frequencies (e.g., higher than 5%) can result from random or species? Classical Darwinian theory states that it is the differential drift. The latter scenario is not unlikely if the risk of schizophrenia in survival and reproduction of individual organisms that drives the the population is determined by thousands of genetic variants. evolutionary process [Darwin, 1859]. However, natural selection Though some theories cannot on their own explain the mainte- can operate simultaneously at different levels of the biological nance of harmful genetic variation in the population, they do hierarchy (multi-level selection theory [Damuth and Heisler, provide a framework that allows us to understand how evolution 1988]. 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