Smeland Olav B, Frei Oleksandr, Kauppi Karolina, Hill W David, Li Wen, Wang Yunpeng, Krull Florian, Bettella Francesco, Eriksen Jon A, Witoelar Aree, Davies Gail, Fan Chun C, Thompson Wesley K, Lam Max, Lencz Todd, Chen Chi-Hua, Ueland Torill, Jönsson Erik G, Djurovic Srdjan, Deary Ian J, Dale Anders M, Andreassen Ole A
Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
JAMA Psychiatry. 2017 Oct 1;74(10):1065-1075. doi: 10.1001/jamapsychiatry.2017.1986.
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.
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).
Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined.
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.
The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.
精神分裂症与广泛的认知障碍相关。尽管认知缺陷是精神分裂症中与功能结局关联最紧密的因素之一，但目前的治疗策略在很大程度上未能改善这些障碍。为了在精神分裂症患者中制定更有效的治疗策略，需要更好地理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。
确定共同影响精神分裂症以及反应时间和言语数字推理等认知领域，以及一般认知功能（一种反映跨认知领域表现的共同变异的表型）的基因组区域。
设计、设置和参与者：使用条件错误发现率分析将来自多个表型的全基因组关联研究的数据相结合，可增强发现遗传变异的能力，并能阐明共享的分子遗传机制。合并了以下于2014年7月24日至2017年1月17日发表的全基因组关联研究的数据：精神疾病基因组学联盟队列中的精神分裂症（n = 79757 [病例，34486；对照，45271]）；英国生物银行队列中的言语数字推理（n = 36035）和反应时间（n = 111483）；以及CHARGE（基因组流行病学心脏与衰老研究队列）（n = 53949）和COGENT（认知基因组学联盟）（n = 27888）中的一般认知功能。
通过条件错误发现率分析确定的遗传位点。确定了脑信使核糖核酸表达和脑表达定量性状位点功能。
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位点：精神分裂症与言语数字推理之间共享2个位点，精神分裂症与反应时间之间共享6个位点，精神分裂症与一般认知功能之间共享14个位点。一个位点在精神分裂症与2种认知特征之间共享，代表检测到的最强共享信号（最接近的基因TCF20；染色体22q13.2），并且在精神分裂症（z值，5.01；P = 5.53×10⁻⁷）、一般认知功能（z值，-4.43；P = 9.42×10⁻⁶）和言语数字推理（z值，-5.43；P = 5.64×10⁻⁸）之间共享。对于18个位点，精神分裂症风险等位基因与较差的认知表现相关。所涉及的基因在发育中和成人大脑中表达。在成人大脑中为4个位点确定了可重复的表达定量性状位点功能。
发现的位点增进了对精神分裂症和认知功能共同遗传基础的理解，提示了新的分子遗传机制。
