Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis

Loh, Po−Ru; Bhatia, Gaurav; Gusev, Alexander; Finucane, Hilary; Bulik-Sullivan, Brendan; Pollack, Samuela; Candia, Teresa R de; Lee, Sang; Wray, Naomi R.; Kendler, Kenneth S.; O'Donovan, Michael Conlon; Neale, Benjamin M.; Patterson, Nick; Price, Alkes L.

doi:10.1038/ng.3431

Cited by 454 publications

(557 citation statements)

References 66 publications

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“…These risk loci are enriched in genes containing de novo mutations in schizophrenia, autism (MIM: 209850), and intellectual disability, 15 and several identified loci contain genes relevant to major hypotheses of schizophrenia etiology, including DRD2 (MIM: 126450; the target of antipsychotic drugs) and genes involved in glutamatergic neurotransmission (GRM3 15 One of the most striking findings that emerged early in schizophrenia studies-at the stage where there were only a handful of genome-wide-significant loci-was the highly polygenic nature of the common variants contributing to risk. 14 This observation has been widely replicated, and estimates are that 71% of 1 Mb genomic regions have at least one variant influencing schizophrenia risk, 53 and there is evidence of substantial pleiotropy with other psychiatric disorders. 26 However, genetic architecture, described as the mix of rare and common variants, is likely to differ between psychiatric disorders, as is already being observed for the higher rates of rare, de novo penetrant CNVs and single-nucleotide variants found in autism than in schizophrenia or bipolar disorder.…”

Section: Schizophreniamentioning

confidence: 98%

“…Estimates from data available to date provide the first evidence for different genetic architectures between diseases, 50 for example, there is more signal from rare variants for amyotrophic lateral sclerosis (motor neuron disease [MIM: 105400]) than for schizophrenia 51 and more predicted loci for schizophrenia than for immune disorders 52 and hypertension. 53 Theoretical and empirical observations suggest a place for non-additive genetic variation, and there have been many largely unsuccessful attempts to detect epistasis with GWAS data. There are a number of likely explanations.…”

Section: Pleiotropy Is Pervasivementioning

confidence: 99%

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10 Years of GWAS Discovery: Biology, Function, and Translation

Visscher

Wray

Zhang

et al. 2017

The American Journal of Human Genetics

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2,536

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Section: Schizophreniamentioning

confidence: 98%

Section: Pleiotropy Is Pervasivementioning

confidence: 99%

10 Years of GWAS Discovery: Biology, Function, and Translation

Visscher

Wray

Zhang

et al. 2017

The American Journal of Human Genetics

2,913

2,536

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“…[52][53][54][55][56] Second, stratified LD-score regression analyzes summary-level data and thus does not take advantage of the additional information available in individual-level data. Although functional-enrichment analyses of individual-level data can be performed with restricted maximum likelihood (REML) and its extensions, [57][58][59] those methods are applicable only to a small number of non-overlapping functional annotations; to our knowledge, all current methods that are applicable to a large number of overlapping functional annotations are based on summary statistics, 60 whereas analyzing one annotation at a time can produce severely biased results (see Figure 2b from Finucane et al…”

Section: Discussionmentioning

confidence: 99%

Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues

Liu

Finucane

Gusev

et al. 2017

The American Journal of Human Genetics

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Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD-score regression that produces robust results in simulations. The top enriched functional categories in local regulation of peripheral-blood gene expression included coding regions (11.413), conserved regions (4.673), and four histone marks (p < 5 3 10 À5 for all enrichments); local enrichments were similar across the 15 tissues.We also observed substantial enrichments for distal regulation of peripheral-blood gene expression: coding regions (4.473), conserved regions (4.513), and two histone marks (p < 3 3 10 À7 for all enrichments). Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Our results elucidate the functional components of the genetic architecture of local and distal regulation of gene expression.

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“…It is striking that our study provides strong statistical evidence for the aggregate effect across 3,915 EGs impacting risk for this neurodevelopmental disorder. A recent SNP-based heritability study reported the extreme polygenicity of schizophrenia, with 70% of 1-Mb genomic regions harboring schizophrenia risk alleles (49). Assuming a similar genetic architecture in ASD and schizophrenia, genomic maps of EGs with "surviving" deleterious and regulatory variants in ASD probands represent a complementary approach for the analysis of combinations of culprit genes or alleles.…”

Section: B C Amentioning

confidence: 99%

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre-and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.essential genes | mouse knockouts | mutational burden | autism spectrum disorder | coexpression modules A utism spectrum disorder (ASD) is a heterogeneous, heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior (1, 2). The highly polygenic nature of ASD (3-5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function. Prioritization of ASD risk genes initially focused on known pathways with recognized relevance to pathogenesis of ASD, such as synaptic function and neuronal development (6). However, combined analyses of de novo, inherited, and case-control variation in over 2,500 ASD parentchild nuclear families identified around 100 genes contributing to ASD risk (7-9), converging on pathways implicated in transcriptional regulation and chromatin modeling in addition to synaptic function.The main challenge in the current understanding of genetic architecture of ASD comes from a need to study the interplay between variants with a high effect (for example, recurrent de novo variants) and a background of variants with an intermediate effect but that nevertheless still disrupt proper neuronal development. Essential genes (EGs) or genes that are necessary for successful completion of pre-and postnatal development are prime candi...

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Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis

Cited by 454 publications

References 66 publications

10 Years of GWAS Discovery: Biology, Function, and Translation

10 Years of GWAS Discovery: Biology, Function, and Translation

Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues

Increased burden of deleterious variants in essential genes in autism spectrum disorder

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