Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
Am J Psychiatry. 2010 Oct;167(10):1254-63. doi: 10.1176/appi.ajp.2010.09091335. Epub 2010 Aug 16.
Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders.
The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders.
The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder.
This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.
家族和双胞胎研究表明，遗传因素对精神分裂症和心境障碍有很大的影响。连锁和候选基因研究也表明，精神分裂症、双相情感障碍和重度抑郁症之间存在重叠。本研究旨在应用全基因组关联研究（GWAS）分析来解决这些疾病遗传效应的特异性问题。
作者结合了三项大型精神分裂症有效性研究（CATIE，基因分型：N=741）、双相情感障碍（STEP-BD，基因分型：N=1,575）和重度抑郁症（STAR*D，基因分型：N=1,938）的 GWAS 数据，以及精神科筛选的对照受试者（NIMH-Genetics Repository：N=1,204）。采用两阶段分析程序，包括病例组和对照组之间等位基因频率差异的全基因组检验，然后进行模型选择步骤，以确定跨疾病的最佳等位基因效应模型。
最显著的结果是在肾上腺髓质素（ADM）基因附近的一个单核苷酸多态性（rs6484218）中看到的，最佳拟合模型表明该效应是双相情感障碍 II 型特有的。研究结果还表明，有几个基因可能具有超越临床诊断边界的效应，包括 NPAS3 中的变异，这些变异在精神分裂症、双相情感障碍和重度抑郁症中表现出多效性效应。
本研究首次提供了全基因组显著证据，表明染色体 11p15 上 ADM 基因附近的变体与精神病理学有关，其效应似乎是双相情感障碍 II 型特有的。尽管没有检测到跨疾病效应的全基因组显著证据，但研究结果提供了证据表明，主要精神疾病存在多效性和疾病特异性效应，并说明了一种分析心境和精神病遗传基础的方法，这可以为未来的大规模跨疾病 GWAS 分析提供信息。
