Importance  Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction.

Objective  To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains.

Design, Setting, and Participants  Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888).

Main Outcomes and Measures  Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined.

Results  Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 × 10⁻⁷), general cognitive function (z score, –4.43; P = 9.42 × 10⁻⁶), and verbal-numerical reasoning (z score, –5.43; P = 5.64 × 10⁻⁸). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain.

Conclusions and Relevance  The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

重要性  精神分裂症与广泛的认知障碍有关。尽管认知缺陷是与精神分裂症功能结果最密切相关的因素之一，但目前的治疗策略在很大程度上无法改善这些损伤。为了对精神分裂症患者制定更有效的治疗策略，需要更好地了解这些认知缺陷的发病机制。越来越多的证据表明，精神分裂症的遗传风险可能导致认知功能障碍。

目的  确定共同影响精神分裂症的基因组区域、反应时间和语言-数字推理的认知领域，以及一般认知功能，这是一种捕获跨认知领域表现的共同变化的表型。

设计、设置和参与者  使用条件性错误发现率分析结合来自多种表型的全基因组关联研究的数据，可以提高发现遗传变异的能力，并可以阐明共享的分子遗传机制。合并了 2014 年 7 月 24 日至 2017 年 1 月 17 日发表的以下全基因组关联研究的数据：精神病基因组学联盟队列中的精神分裂症（n = 79 757 [病例，34 486；对照组，45 271]） ; 英国生物银行队列中的语言-数字推理（n = 36 035）和反应时间（n = 111 483）；CHARGE（基因组流行病学心脏和衰老研究队列）（n = 53 949）和 COGENT（认知基因组学联盟）（n = 27 888）中的一般认知功能。

主要结果和措施  通过条件错误发现率分析确定的基因位点。确定脑信使RNA表达和脑表达数量性状基因座功能。

结果  在全基因组关联研究的参与者中，确定了 21 个共同影响精神分裂症和认知特征的基因座：2 个在精神分裂症和语言-数字推理之间共享，6 个在精神分裂症和反应时间之间共享，14 个在精神分裂症和认知特征之间共享。一般认知功能。1 个基因座在精神分裂症和 2 个认知特征之间共享，代表检测到的最强共享信号（最近的基因TCF20；染色体 22q13.2），在精神分裂症（z评分，5.01；P  = 5.53 × 10 ^-7）、一般认知函数（z得分，–4.43；P  = 9.42 × 10 ^-6）和语言-数字推理（z分数，–5.43；P  = 5.64 × 10 ^-8）。对于 18 个基因座，精神分裂症风险等位基因与较差的认知表现相关。相关基因在发育和成人大脑中表达。在成人大脑中确定了 4 个基因座的可复制表达数量性状基因座功能。

结论和相关性  发现的基因座提高了对精神分裂症和认知功能的共同遗传基础的理解，提出了新的分子遗传机制。