Cross-ancestry analysis of brain QTLs enhances interpretation of schizophrenia genome-wide association studies.

IF 8.1 1区 生物学 Q1 GENETICS & HEREDITY American journal of human genetics Pub Date : 2024-11-07 Epub Date: 2024-10-02 DOI:10.1016/j.ajhg.2024.09.001
Yu Chen, Sihan Liu, Zongyao Ren, Feiran Wang, Qiuman Liang, Yi Jiang, Rujia Dai, Fangyuan Duan, Cong Han, Zhilin Ning, Yan Xia, Miao Li, Kai Yuan, Wenying Qiu, Xiao-Xin Yan, Jiapei Dai, Richard F Kopp, Jufang Huang, Shuhua Xu, Beisha Tang, Lingqian Wu, Eric R Gamazon, Tim Bigdeli, Elliot Gershon, Hailiang Huang, Chao Ma, Chunyu Liu, Chao Chen
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Abstract

Research on brain expression quantitative trait loci (eQTLs) has illuminated the genetic underpinnings of schizophrenia (SCZ). Yet most of these studies have been centered on European populations, leading to a constrained understanding of population diversities and disease risks. To address this gap, we examined genotype and RNA-seq data from African Americans (AA, n = 158), Europeans (EUR, n = 408), and East Asians (EAS, n = 217). When comparing eQTLs between EUR and non-EUR populations, we observed concordant patterns of genetic regulatory effect, particularly in terms of the effect sizes of the eQTLs. However, 343,737 cis-eQTLs linked to 1,276 genes and 198,769 SNPs were found to be specific to non-EUR populations. Over 90% of observed population differences in eQTLs could be traced back to differences in allele frequency. Furthermore, 35% of these eQTLs were notably rare in the EUR population. Integrating brain eQTLs with SCZ signals from diverse populations, we observed a higher disease heritability enrichment of brain eQTLs in matched populations compared to mismatched ones. Prioritization analysis identified five risk genes (SFXN2, VPS37B, DENR, FTCDNL1, and NT5DC2) and three potential regulatory variants in known risk genes (CNNM2, MTRFR, and MPHOSPH9) that were missed in the EUR dataset. Our findings underscore that increasing genetic ancestral diversity is more efficient for power improvement than merely increasing the sample size within single-ancestry eQTLs datasets. Such a strategy will not only improve our understanding of the biological underpinnings of population structures but also pave the way for the identification of risk genes in SCZ.

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脑QTL的交叉雌雄分析增强了对精神分裂症全基因组关联研究的解释。
大脑表达定量性状位点(eQTLs)研究揭示了精神分裂症(SCZ)的遗传基础。然而,这些研究大多以欧洲人群为中心,导致对人群多样性和疾病风险的理解受到限制。为了填补这一空白,我们研究了非裔美国人(AA,n = 158)、欧洲人(EUR,n = 408)和东亚人(EAS,n = 217)的基因型和 RNA-seq 数据。在比较欧洲人和非欧洲人的 eQTLs 时,我们观察到了遗传调控效应的一致模式,尤其是在 eQTLs 的效应大小方面。然而,与 1,276 个基因和 198,769 个 SNP 相连的 343,737 个顺式 eQTLs 被发现是非欧洲共同体人群所特有的。在观察到的 eQTLs 群体差异中,90% 以上可追溯到等位基因频率的差异。此外,这些eQTLs中有35%在欧洲人群中非常罕见。将脑部eQTL与来自不同人群的SCZ信号进行整合,我们观察到,与不匹配人群相比,匹配人群中脑部eQTL的疾病遗传富集度更高。优先级分析确定了五个风险基因(SFXN2、VPS37B、DENR、FTCDNL1 和 NT5DC2)和三个已知风险基因(CNNM2、MTRFR 和 MPHOSPH9)中的潜在调控变异,这些变异在 EUR 数据集中被遗漏。我们的研究结果表明,增加遗传祖先的多样性比仅仅增加单基因eQTLs数据集的样本量更能提高研究的效率。这种策略不仅能提高我们对种群结构生物学基础的理解,还能为鉴定 SCZ 的风险基因铺平道路。
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来源期刊
CiteScore
14.70
自引率
4.10%
发文量
185
审稿时长
1 months
期刊介绍: The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.
期刊最新文献
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