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Chromosome 8P As a Potential Hub for Developmental Neuropsychiatric

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Chromosome 8P As a Potential Hub for Developmental Neuropsychiatric Molecular Psychiatry (2009) 14, 563–589 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp FEATURE REVIEW Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer R Tabare´s-Seisdedos1 and JLR Rubenstein2 1Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, CIBER-SAM, University of Valencia, Valencia, Spain and 2Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA, USA Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying suscept- ibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson’s and Alzheimer’s disease) and cancer. Furthermore, at least seven nonprotein- coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence. Molecular Psychiatry (2009) 14, 563–589; doi:10.1038/mp.2009.2; published online 10 February 2009 Keywords: 8p; NRG1; FGF family; schizophrenia; autism; cancer Introduction has the potential to improve the quality of life for many people.5,6 Autism and schizophrenia are complex neuropsy- The assumption that neuropsychiatric disorders are chiatric syndromes affecting between 0.3 and 0.6% of phenotypically heterogeneous with overlapping find- children and approximately 1% of the adult world ings suggests the participation of more than one population.1,2 These disorders are chronic, debilitat- etiological factor and pathophysiological process, ing conditions with profound human and economic some of them being partly shared across the tradi- consequences.3,4 Therefore, each discovery that tional classification categories.7,8 Probably, as in further elucidates disease mechanisms, and each human cancers, the heterogeneity in clinical results new molecular diagnostic test or therapeutic advance and treatment outcomes stems directly from the underlying variation in disorder biology.9 It is no wonder then that this remarkable biologic hetero- geneity of autism (autism spectrum disorders), schi- Correspondence: Professor Dr R Tabare´s-Seisdedos. Teaching Unit zophrenia (schizophrenias) or bipolar disorder of Psychiatry and Psychological Medicine, Department of Med- icine, University of Valencia, CIBER-SAM, Blasco-Iba´n˜ ez 17, (bipolar spectrum) is intimately related to the com- 46010 Valencia, Spain and Professor Dr John LR Rubenstein. Nina plexity of the genetic control of brain development Ireland Laboratory of Developmental Neurobiology, Department and function. For instance, several of the suscept- of Psychiatry, University of California, San Francisco, CA 94143, ibility loci and genes in these disorders play a USA. principal role in the development, plasticity and E-mails: [email protected] and [email protected] 10–13 Received 1 August 2008; revised 19 December 2008; accepted 7 maintenance of the central nervous system (CNS). January 2009; published online 10 February 2009 However, the molecular mechanics, the neural Chromosome 8p as a potential hub for neuropsychiatric disorders R Tabare´s-Seisdedos and JLR Rubenstein 564 systems and the concepts used are, with few excep- affected by the identified structural variants encode tions, excessively vague.14,15 proteins that have been shown to mediate response to Recognizing these limitations and approaches, we environmental challenge (‘environmental sensor focus our attention on the 8p chromosome region for genes’), such as immune response, perception of several reasons. First, human chromosome 8 spans smell and perception of chemical stimuli.22,23 It is approximately 145 million base pairs (bp), which interesting to take note of the presence of olfactory represents between 4.5 and 5.0% of the genome. The dysfunction in autism24 and schizophrenia sub- short arm spans approximately 45.2 million base pairs jects.25,26 Furthermore, these neuropsychiatric disor- and only represents 1.5% of the genome, and includes ders may be associated with various immune system 484 genes (110 pseudogenes). Many of these genes anomalies.27,28 The new generation sequencing tech- encode proteins that control cell proliferation, apop- nologies have detected 343 copy number variations of tosis or both, and may play important roles in several 146 genes on chromosome 8p. Several of these genes normal and pathological processes such as develop- CNVs have been associated with schizophrenia,10 ment or signaling in the CNS and immune response, autism spectrum disorders,29 cancer21,30 and Crohn’s and cancer and developmental neuropsychiatric dis- disease31 (for updated summary, see Supplementary orders, respectively. Currently, it is estimated that Table S4). It is noted that, 8p is also enriched in there are approximately 41 (8.47%) genes on chromo- single-nucleotide variants across the entire gen- some 8p involved in the genetic control of cerebral ome.32,33 The short arm of chromosome 8p is one of development and function, and approximately the most enriched regions in structural and single- 80 (15.53%) genes involved in cancer biology nucleotide variation across the human genome, but, (see Table 1 and Supplementary Table S1 at Supple- in any case, little is known about the role of such mentary Information). It is important to bear in mind genetic diversity in disease association. that 8p has lower rates of base pairs and genes than Third, given that there are genetic factors to other chromosomal regions with significant linkage to schizophrenia and other major neuropsychiatric schizophrenia (1q, 6p and 22q), autism (7q and 15q) disorders, the remaining questions are which are the and bipolar disorder (13q). Only 18p, associated with related chromosomal regions and how will the genes bipolar disorder risk, has lower rates than 8p be identified?34 In relation to this, 8p is among the (Supplementary Table S2). Although chromosome 8 best-supported genomic regions implicated in schizo- is typical in several characteristics, such as length, phrenia and bipolar risk,35–40 as well as in other gene or repeat content, a unique feature of this important human diseases such as cancer.41,42 For chromosome is a big region of approximately 15 example, the ‘Top Results’ list of Schizophrenia Gene megabases on distal 8p that appears to have a high Database,43,44 displaying the 27 genes most strongly mutation rate. Likewise, this distal subregion on 8p associated with schizophrenia, includes three 8p shows an immense divergence between human and genes (1st VMAT1/SLC18A1; 15th NRG1; 26th chimpanzee, suggesting that the high mutation rates PPP3CC). It is noted that, it is the chromosome at distal 8p have contributed to the evolution of the region (arm) with a greater number of schizophrenia primate brain.16 Interestingly, a high mutation rate has susceptibility genes in this ranking. In addition, Bray been associated with high homologous recombination et al.45 observed that variant(s) within 8p may in the human genome.17 Consequently, an extraordin- modulate schizophrenia risk though a transacting ary recombination rate could increase the duplication effect on dystrobrevin-binding protein 1 (DTNBP1) genetic process, and allow us a better understanding expression. DTNBP1 is one of the best-supported of the biological connections between 8p, cancer and susceptibility genes for schizophrenia, bipolar mental illness at a molecular level. disorder and major depressive disorder.40,46–48 These Second, various studies have recently evaluated the data provide complementary evidence for chromo- contribution of structural variation of DNA (that is, some 8p as a neuropsychiatry susceptibility locus. insertions and deletions of DNA, collectively termed Fourth, the animal models of human behavioral copy number variants (CNVs), as well as balanced disorders represent an obvious step forward in the rearrangements such as inversions) in the human arena of the study of the genetics of behavioral genetic variability and in the susceptibility to com- domains.49 We recently described a mouse mutant mon and complex diseases such as cancer, obesity or that lacks the
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