Charney A W, Ruderfer D M, Stahl E A, Moran J L, Chambert K, Belliveau R A, Forty L, Gordon-Smith K, Di Florio A, Lee P H, Bromet E J, Buckley P F, Escamilla M A, Fanous A H, Fochtmann L J, Lehrer D S, Malaspina D, Marder S R, Morley C P, Nicolini H, Perkins D O, Rakofsky J J, Rapaport M H, Medeiros H, Sobell J L, Green E K, Backlund L, Bergen S E, Juréus A, Schalling M, Lichtenstein P, Roussos P, Knowles J A, Jones I, Jones L A, Hultman C M, Perlis R H, Purcell S M, McCarroll S A, Pato C N, Pato M T, Craddock N, Landén M, Smoller J W, Sklar P
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
Transl Psychiatry. 2017 Jan 10;7(1):e993. doi: 10.1038/tp.2016.242.
We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h=0.35; BD II SNP-h=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.
我们对国际双相情感障碍队列集合（ICCBD）中的6447例双相情感障碍（BD）病例和12639例对照进行了全基因组关联研究。对来自精神基因组学联盟双相情感障碍工作组先前结果进行荟萃分析，合并样本包括13902例病例和19279例对照。我们确定了8个全基因组显著关联区域，包括10号染色体上一个新的关联区域（rs10884920；P = 3.28×10），该区域包含脑富集细胞骨架蛋白内收蛋白3（ADD3）、一种非编码RNA和一种神经肽特异性氨肽酶P（XPNPEP1）。我们的大样本量使我们能够测试BD亚型的遗传力和遗传相关性，并研究它们与精神分裂症和重度抑郁症的遗传重叠。我们发现BD两种最常见形式的遗传力存在显著差异（BD I单核苷酸多态性遗传力h = 0.35；BD II单核苷酸多态性遗传力h = 0.25；P = 0.02）。BD I和BD II之间的遗传相关性为0.78，而当比较包含两种类型的BD队列时，遗传相关性为0.97。此外，我们证明与BD II患者相比，BD I患者中精神分裂症和BD的多基因风险等位基因负荷显著更高，与BD I或BD II患者相比，双相型分裂情感障碍患者中精神分裂症风险等位基因负荷更高。这些结果表明，目前定义的BD亚型在遗传结构上存在部分差异。
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