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Genetic Analysis of Schizophrenia and Bipolar Disorder Reveals Polygenicity but Also Suggests New Directions for Molecular Interrogation Benjamin M

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Genetic Analysis of Schizophrenia and Bipolar Disorder Reveals Polygenicity but Also Suggests New Directions for Molecular Interrogation Benjamin M Genetic Analysis of Schizophrenia and Bipolar Disorder Reveals Polygenicity But Also Suggests New Directions for Molecular Interrogation Benjamin M. Neale, PhD1,2 and Pamela Sklar, MD, PhD3 1Analytical and Translational Genetics Unit Psychiatric and Neurodevelopmental Genetics Unit Department of Medicine, Massachusetts General Hospital Harvard Medical School Boston, Massachusetts 2Stanley Center for Psychiatric Research Program in Medical and Population Genetics Broad Institute of Harvard and MIT Cambridge, Massachusetts 3Division of Psychiatric Genomics Department of Psychiatry, Icahn School of Medicine at Mount Sinai New York, New York © 2015 Neale Genetic Analysis of Schizophrenia and Bipolar Disorder Reveals Polygenicity But Also Suggests New Directions for Molecular Interrogation 53 Introduction to gather information about the genome. The SNP NOTES Schizophrenia and bipolar disorder are among the Consortium (Sachidanandam et al., 2001; Thorisson most debilitating psychiatric illnesses and represent and Stein, 2003) and International HapMap a tremendous public health burden. Nearly a project (International HapMap Consortium, 2003, century ago, Emil Kraepelin delineated two forms 2005, 2007) created a catalog of common DNA of mental illness as “dementia praecox” (now called variations and characterized the genome-wide schizophrenia) and “manic-depressive illness” (now patterns of linkage disequilibrium (LD). LD is a term called bipolar disorder). This dichotomy has been used to describe the correlation between genetic one of the founding principles of modern Western variations, i.e., two variants are said to be in LD if psychiatry, but in recent years, analysis of new the genotypes correlate. The HapMap project, in genetic data is leading to its reexamination. In particular, was a central community-wide resource defining “dementia praecox,” Kraepelin reviewed that made genotype data available for individuals its apparently familial nature, noting a high degree from multiple ethnicities, providing information on of sibling sharing as well as parent offspring sharing, allele frequency and LD across different continental albeit to a lesser extent (Kraepelin, 1919). Thus, even populations. These large-scale evaluations of genetic a century ago, researchers were observing inheritance variation also laid the groundwork for genome- in families for severe mental illness. wide association studies (GWAS) by providing a sufficiently comprehensive set of genetic markers to These early views of schizophrenia and bipolar effectively test genome-wide. disorder as inherited disorders have been refined by almost one hundred years of twin and family studies. The most pervasive type of genetic marker is the These studies demonstrated substantial heritability single nucleotide polymorphism (SNP), which is a (the proportion of disease liability due to genetic single base change in the DNA sequence. GWAS factors) for both schizophrenia (estimates ranging enables a systematic and unbiased population- from 60% to 90%) and bipolar disorder (estimates based evaluation of individual DNA variants ranging from 60% to 80%) and showed that these for association with disease across the genome. disorders can co-occur in families (Berrettini, In GWAS, the classes of genetic variations best 2000; McGuffin et al., 2003; Sullivan et al., 2003; explored have been those that are common in the Lichtenstein et al., 2009). The strong and consistent population (common genetic variants, typically evidence for high heritability suggested that disease with minor allele frequency > 1–5%, depending on genes might be identified using genetic approaches. the study), and this technique has been successfully Linkage, which is one of the earliest methods of applied across a wide range of complex traits. The genetic analysis, works by scanning the genome in array technology used for GWAS also revealed copy search of regions that are shared by family members number variation (large deletions or duplications who are affected by the disease under study. This of DNA from individual chromosomes), which has development spurred many linkage studies to search been shown to confer risk of several psychiatric for schizophrenia and bipolar disorder regions and illnesses including autism, schizophrenia, bipolar the genes within them (Levinson et al., 2003; Lewis disorder, and attention deficit hyperactivity disorder et al., 2003; and Segurado et al., 2003). However, (GAIN Collaborative Research Group et al., 2007; linkage is effective only when there is limited “locus International Schizophrenia Consortium, 2008; heterogeneity” (e.g., if the genetic variation that Williams et al., 2010; Levy et al., 2011; Sanders influences schizophrenia is restricted to a few regions et al., 2011; Malhotra and Sebat, 2012; Ramos- of the genome) or when there are large pedigrees Quiroga et al., 2014; Rees et al., 2014; Stefansson et with a nearly Mendelian cause (i.e., a genetic variant al., 2014; Szatkiewicz et al., 2014). Beyond GWAS, is nearly sufficient to cause disease in all affected next-generation sequencing technologies have members of the pedigree). To date, for schizophrenia been developed that enable the discovery of rare (< and bipolar disorder, linkage has met with no clear 1% minor allele frequency) and private variation success despite the meta-analysis of thousands of (effectively specific to individuals or families), thus samples. These findings indicate that risk variants are extending the application of association tests into not fully causal and that many regions in the genome this range. are likely relevant to both schizophrenia and bipolar disorder. In general, the results from the current GWAS and sequencing studies of schizophrenia and bipolar The past decade of human genetics research has seen disorder clearly show that a great many genetic a staggering technological revolution in our ability variants influence the risk of schizophrenia and © 2015 Neale 54 NOTES bipolar disorder. Both common and rare variants sample used to evaluate the predictive validity of the contribute to the genetic architecture of these PRS) is essential to avoid false-positive associations diseases, and most effect sizes are small to modest, and overestimation of the predictive validity of such necessitating large-scale genetic studies to robustly a score. The PRS from the early GWAS explained identify novel risk factors. The identification of only a small amount of the variance in liability to these genetic variants and the interpretation of the becoming ill with schizophrenia. At present, the biological consequences of said variants will form the PRS score is not sufficiently specific for clinical use. basis for new insights into the pathogenic processes One of the predictions from the work suggested that underlie schizophrenia and bipolar disorder. that increasing sample size would increase the explanatory power of such scores because it would Many Common DNA Variants Play more accurately estimate the true effect size of these a Large Role in Schizophrenia and genetic variants. Bipolar Disorder Not only did the schizophrenia PRS predict The first GWAS of common variants in schizophrenia schizophrenia, but perhaps more surprisingly, it and bipolar disorder identified only a small handful of also showed predictive ability for bipolar disorder, genome-wide significant loci (GAIN Collaborative implying that these two disorders share many more Research Group et al., 2007; O’Donovan et al., genetic risk factors than had been expected. In 2008; International Schizophrenia Consortium et order to quantitate how much genetic overlap exists al., 2009). This limited initial success was driven between schizophrenia and bipolar disorder (and four mainly by the small effect size each variant is other majors forms of psychopathology), genome- likely to have (< 1.5-fold influence on risk) and wide complex trait analysis (GCTA) was performed the comparatively modest sample sizes (< 10,000 (Yang et al., 2011). The basic principle behind individuals). In spite of a relative paucity of strongly GCTA is that if a trait has a genetic component, associated loci (compared with some other traits, like then people who are more phenotypically similar those of Crohn’s disease [Barrett et al., 2008] or age- (e.g., both have schizophrenia) will tend to be more related macular degeneration [Klein et al., 2005]), genetically similar (i.e., they will tend to share risk one of the first large-scale GWAS of schizophrenia alleles for the disease in question). This framework demonstrated a myriad of DNA variants whose enables not only the assessment of evidence for effects are too small to detect individually, but when heritability from common DNA markers across summed together clearly contributed to schizophrenia the genome (rather than using twin and family risk (International Schizophrenia Consortium et al., relationships to tease out genetic contribution 2009). This GWAS provided the first molecular to disease) but also a multivariate approach for evidence that schizophrenia is highly polygenic, and comparing different diseases. Consistent with the subsequently, it has been widely validated in many polygenic prediction work, when schizophrenia and independent samples. bipolar disorder were analyzed jointly using GCTA, there was a substantial overlap in their genetic basis, The many risk variants, when summed in this with a genetic correlation of ~0.7 (Cross-Disorder manner, essentially form a polygenic risk score (PRS). Group
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