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Leveraging Genomic Annotations and Pleiotropic Enrichment for Improved Replication Rates in Schizophrenia GWAS.

Abstract：

:Most of the genetic architecture of schizophrenia (SCZ) has not yet been identified. Here, we apply a novel statistical algorithm called Covariate-Modulated Mixture Modeling (CM3), which incorporates auxiliary information (heterozygosity, total linkage disequilibrium, genomic annotations, pleiotropy) for each single nucleotide polymorphism (SNP) to enable more accurate estimation of replication probabilities, conditional on the observed test statistic ("z-score") of the SNP. We use a multiple logistic regression on z-scores to combine information from auxiliary information to derive a "relative enrichment score" for each SNP. For each stratum of these relative enrichment scores, we obtain nonparametric estimates of posterior expected test statistics and replication probabilities as a function of discovery z-scores, using a resampling-based approach that repeatedly and randomly partitions meta-analysis sub-studies into training and replication samples. We fit a scale mixture of two Gaussians model to each stratum, obtaining parameter estimates that minimize the sum of squared differences of the scale-mixture model with the stratified nonparametric estimates. We apply this approach to the recent genome-wide association study (GWAS) of SCZ (n = 82,315), obtaining a good fit between the model-based and observed effect sizes and replication probabilities. We observed that SNPs with low enrichment scores replicate with a lower probability than SNPs with high enrichment scores even when both they are genome-wide significant (p < 5x10-8). There were 693 and 219 independent loci with model-based replication rates ≥80% and ≥90%, respectively. Compared to analyses not incorporating relative enrichment scores, CM3 increased out-of-sample yield for SNPs that replicate at a given rate. This demonstrates that replication probabilities can be more accurately estimated using prior enrichment information with CM3.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Wang Y,Thompson WK,Schork AJ,Holland D,Chen CH,Bettella F,Desikan RS,Li W,Witoelar A,Zuber V,Devor A,Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium.,Enhancing Neuro Imaging Genetics throug

doi

10.1371/journal.pgen.1005803

subject

Has Abstract

pub_date

2016-01-25 00:00:00

pages

e1005803

issue

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-15-01167

journal_volume

pub_type

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Leveraging Genomic Annotations and Pleiotropic Enrichment for Improved Replication Rates in Schizophrenia GWAS.