Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
JAMA Psychiatry. 2014 Jun;71(6):647-56. doi: 10.1001/jamapsychiatry.2014.157.
One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation.
To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals.
DESIGN, SETTING, AND PARTICIPANTS: Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals.
We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts.
The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10(-10)). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10(-9)). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects.
The findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.
研究与精神分裂症相关的行为和生物学表型，可能与遗传变异更直接相关，这是理解精神分裂症遗传复杂性的一种方法。
鉴定与精神分裂症患者和对照个体的一般认知能力（g）相关的单核苷酸多态性。
设计、环境和参与者：全基因组关联研究，随后对未受影响的兄弟姐妹和独立的精神分裂症样本进行分析、体内大脑生理学的功能磁共振成像研究以及死后脑组织样本的 RNA 测序。发现队列和未受影响的兄弟姐妹是美国国立精神卫生研究所临床大脑疾病分部精神分裂症遗传学研究的参与者。其他精神分裂症队列来自美国、日本和德国的精神科治疗环境。发现队列包括 339 名精神分裂症患者和 363 名社区对照参与者。后续分析研究了 147 名精神分裂症病例的未受影响的兄弟姐妹和包括另外 668 名参与者在内的独立精神分裂症样本。成像分析包括 87 名精神分裂症病例和 397 名对照个体。脑组织样本可用于 64 例病例和 61 例对照个体。
我们在发现队列中按组研究了 g 的全基因组关联。我们使用了选定的基因型来测试未受影响的兄弟姐妹和独立的精神分裂症样本中的特定关联。成像分析集中在工作记忆期间前额叶皮层的激活。脑组织研究产生了 RefSeq 转录物的信使 RNA 表达水平。
精神分裂症发现队列显示 g 与钠通道基因 SCN2A 的多态性存在全基因组显著关联，占 g 变异的 10.4%（rs10174400，P = 9.27×10(-10)）。对照个体显示 g/基因型关联呈反向等位基因方向性趋势。基因型-组间相互作用也具有全基因组显著性（P = 1.75×10(-9)）。兄弟姐妹显示出与精神分裂症组平行的与认知相关的基因型关联和相同的相互作用模式。在独立的精神分裂症样本中也发现了与认知相关的类似的基因型关联。成像分析显示出按组和基因型-组间相互作用的相似的基因型关联模式。大脑中 RNA 的测序显示，在患者组中，2 个 SCN2A 替代转录本的表达减少，且具有基因型-组间相互作用，这再次与认知效应平行。
研究结果表明 SCN2A 和钠通道生物学与精神分裂症患者和未受影响的亲属的认知障碍有关，可能有助于开发认知增强治疗方法。
