A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases.
A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases.
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DOI：
10.1038/ng.3572
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发表时间：
2016-07
期刊：
影响因子：
30.8
通讯作者：
Raychaudhuri S
中科院分区：
文献类型：
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作者：
Han B;Pouget JG;Slowikowski K;Stahl E;Lee CH;Diogo D;Hu X;Park YR;Kim E;Gregersen PK;Dahlqvist SR;Worthington J;Martin J;Eyre S;Klareskog L;Huizinga T;Chen WM;Onengut-Gumuscu S;Rich SS;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium;Wray NR;Raychaudhuri S
越来越多的证据表明，包括自身免疫和神经精神疾病在内的复杂特征（多效性）之间存在共同的风险等位基因。这可能是由于所有个体之间的共享（全群多效性），或遗传异质性队列中的个体子集（亚群异质性）。BUHMBOX是利用基因型数据区分这两种情况的有效统计方法。我们观察到11种自身免疫性疾病与1型糖尿病（T1D, p<10−4），11种自身免疫性疾病与类风湿关节炎（RA, p<10−3）之间存在共同的遗传基础。这种共享不能用亚组异质性来解释（修正后的pBUHMBOX >.2, 6,670例T1D和7,279例RA）。血清阴性和血清阳性RA之间的遗传共享（p<10−9）具有显著的亚组异质性，表明在血清阴性病例中存在血清阳性样病例亚组（pBUHMBOX=0.008, 2,406例血清阴性RA）。我们还观察到重度抑郁症（MDD）和精神分裂症之间存在共同的遗传基础（p<10−4），这不能用亚组异质性来解释（9238例MDD病例的pBUHMBOX=0.28）。
There is growing evidence of shared risk alleles between complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing between all individuals (whole-group pleiotropy), or a subset of individuals within a genetically heterogeneous cohort (subgroup heterogeneity). BUHMBOX is a well-powered statistic distinguishing between these two situations using genotype data. We observed a shared genetic basis between 11 autoimmune diseases and type 1 diabetes (T1D, p<10−4), and 11 autoimmune diseases and rheumatoid arthritis (RA, p<10−3). This sharing was not explained by subgroup heterogeneity (corrected pBUHMBOX>0.2, 6,670 T1D cases and 7,279 RA cases). Genetic sharing between seronegative and seropostive RA (p<10−9) had significant evidence of subgroup heterogeneity, suggesting a subgroup of seropositive-like cases within seronegative cases (pBUHMBOX=0.008, 2,406 seronegative RA cases). We also observed a shared genetic basis between major depressive disorder (MDD) and schizophrenia (p<10−4) that was not explained by subgroup heterogeneity (pBUHMBOX=0.28 in 9,238 MDD cases).