Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders.

Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders.
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条件GWAS分析鉴定精神疾病的疾病特异性snp。

DOI:
10.1038/s41380-020-0705-9
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发表时间:
2021-06
影响因子:
11
通讯作者:
Wray NR
Wray NR
中科院分区:
医学1区
文献类型:
--
作者:
Byrne EM;Zhu Z;Qi T;Skene NG;Bryois J;Pardinas AF;Stahl E;Smoller JW;Rietschel M;Bipolar Working Group of the Psychiatric Genomics Consortium;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium;Owen MJ;Walters JTR;O'Donovan MC;McGrath JG;Hjerling-Leffler J;Sullivan PF;Goddard ME;Visscher PM;Yang J;Wray NR

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大量的遗传易感性在精神疾病中是共享的,但对特定疾病的风险变体知之甚少。我们使用多性状条件和联合分析(mtCOJO)来调整一种疾病的GWAS汇总统计量,以确定假定的疾病特异性SNP关联。我们将mtCOJO应用于精神病基因组学联盟的五种精神疾病的汇总统计-精神分裂症(SCZ),双相情感障碍(BIP),重度抑郁症(MD),注意力缺陷多动障碍(ADHD)和自闭症(AUT)。这些疾病的大多数全基因组显著变体具有多效性的证据(即,对多种精神疾病的影响),因此减少了mtCOJO条件效应量。然而,全基因组显著变异的子集具有更大的条件效应大小,与疾病特异性效应一致:130个全基因组显著变异中有15个用于精神分裂症,40个中有5个用于重度抑郁症,11个中有3个用于ADHD,2个中有1个用于自闭症。我们发现VPS 29在脑中的表达降低可能仅增加SCZ的风险,CSE 1 L的表达增加与SCZ和MD相关,但与BIP无关。同样,大脑中PCDHA 7表达的减少与MD风险增加有关,但与SCZ和BIP风险降低有关。
Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium – schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genome-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. We show that decreased expression of VPS29 in the brain may increase risk to SCZ only and increased expression of CSE1L is associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7 in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.
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影响因子: 9.8
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