Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate

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.

多项证据表明，全基因组关联研究（genome-wide association studies, GWAS）有潜力解释更多常见复杂表型的“遗传力缺失”现象。然而，当前仍缺乏可靠方法来鉴定更多影响疾病风险的单核苷酸多态性（single nucleotide polymorphisms, SNPs）。本研究针对全基因组关联研究汇总统计数据，采用基于遗传多效性的条件错误发现率（genetic pleiotropy-informed conditional false discovery rate, FDR）方法，鉴定与精神分裂症（schizophrenia, SCZ）和双相情感障碍（bipolar disorders, BD）相关的新位点——这两种疾病均为高遗传力且存在显著遗传力缺失的复杂精神疾病。流行病学与临床证据表明，精神分裂症与双相情感障碍具有相似的疾病特征，且存在重叠的致病基因。本研究对精神病基因组学联盟（Psychiatric Genome Consortium）的数据集计算了条件分位数-分位数（Q–Q）曲线：精神分裂症组包含9379例病例与7736例对照，双相情感障碍组包含6990例病例与4820例对照。结果显示，随着与其中一种疾病的关联强度变化，与另一种疾病相关的单核苷酸多态性呈现富集趋势，同时错误发现率（FDR）也相应降低。应用该条件错误发现率方法，我们在条件错误发现率阈值0.05以下鉴定到58个与精神分裂症相关的位点，以及35个与双相情感障碍相关的位点。其中，有14个位点同时与精神分裂症和双相情感障碍相关（联合错误发现率，conjunction FDR）。综上，本研究结果证实了基于遗传多效性的方法可提升精神分裂症与双相情感障碍的基因发现效率，并表明这两种疾病存在重叠的遗传机制。