Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis
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Open Access
- 2 November 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 47 (12), 1385-1392
- https://doi.org/10.1038/ng.3431
Abstract
Po-Ru Loh, Alkes Price and colleagues developed a fast algorithm for multicomponent, multi-trait variance-components analysis and use it to analyze the genetic architectures of schizophrenia and nine complex diseases from the PGC and GERA cohorts. Their analyses support a largely polygenic architecture for schizophrenia and significant genetic correlations for several pairs of GERA diseases. Heritability analyses of genome-wide association study (GWAS) cohorts have yielded important insights into complex disease architecture, and increasing sample sizes hold the promise of further discoveries. Here we analyze the genetic architectures of schizophrenia in 49,806 samples from the PGC and nine complex diseases in 54,734 samples from the GERA cohort. For schizophrenia, we infer an overwhelmingly polygenic disease architecture in which ≥71% of 1-Mb genomic regions harbor ≥1 variant influencing schizophrenia risk. We also observe significant enrichment of heritability in GC-rich regions and in higher-frequency SNPs for both schizophrenia and GERA diseases. In bivariate analyses, we observe significant genetic correlations (ranging from 0.18 to 0.85) for several pairs of GERA diseases; genetic correlations were on average 1.3 tunes stronger than the correlations of overall disease liabilities. To accomplish these analyses, we developed a fast algorithm for multicomponent, multi-trait variance-components analysis that overcomes prior computational barriers that made such analyses intractable at this scale.Keywords
This publication has 64 references indexed in Scilit:
- Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common DiseasesAmerican Journal of Human Genetics, 2014
- Genome-wide association analysis identifies 13 new risk loci for schizophreniaNature Genetics, 2013
- Genetic relationship between five psychiatric disorders estimated from genome-wide SNPsNature Genetics, 2013
- Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihoodBioinformatics, 2012
- Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPsNature Genetics, 2012
- Genome-wide association study identifies five new schizophrenia lociNature Genetics, 2011
- Genome partitioning of genetic variation for complex traits using common SNPsNature Genetics, 2011
- Estimating Missing Heritability for Disease from Genome-wide Association StudiesAmerican Journal of Human Genetics, 2011
- GCTA: A Tool for Genome-wide Complex Trait AnalysisAmerican Journal of Human Genetics, 2011
- Common SNPs explain a large proportion of the heritability for human heightNature Genetics, 2010