Andreassen Ole A, Thompson Wesley K, Schork Andrew J, Ripke Stephan, Mattingsdal Morten, Kelsoe John R, Kendler Kenneth S, O'Donovan Michael C, Rujescu Dan, Werge Thomas, Sklar Pamela, Roddey J Cooper, Chen Chi-Hua, McEvoy Linda, Desikan Rahul S, Djurovic Srdjan, Dale Anders M
KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
PLoS Genet. 2013 Apr;9(4):e1003455. doi: 10.1371/journal.pgen.1003455. Epub 2013 Apr 25.
Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q-Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versa with a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders.
多条证据表明，全基因组关联研究（GWAS）有潜力解释更多常见复杂表型的“缺失遗传率”。然而，目前缺乏可靠的方法来识别更大比例的影响疾病风险的单核苷酸多态性（SNP）。在此，我们对GWAS汇总统计数据使用一种基于遗传多效性的条件错误发现率（FDR）方法，以识别与精神分裂症（SCZ）和双相情感障碍（BD）相关的新基因座，这两种高度遗传的疾病存在显著的缺失遗传率。流行病学和临床证据表明SCZ和BD之间具有相似的疾病特征和重叠基因。在此，我们计算了精神基因组联盟数据的条件Q-Q曲线（SCZ：n = 9379例，n = 7736例对照；BD：n = 6990例，n = 4820例对照），以显示与SCZ相关的SNP随着与BD的关联而富集，反之亦然，同时相应降低FDR。应用条件FDR方法，我们在条件FDR水平为0.05以下识别出58个与SCZ相关的基因座和35个与BD相关的基因座。其中，14个基因座与SCZ和BD均相关（联合FDR）。这些发现共同表明了基于遗传多效性的方法在改善SCZ和BD基因发现方面的可行性，并表明这两种疾病之间存在重叠的遗传机制。
