META-ANALYSIS OF RARE CNV GENOME-WIDE ASSOCIATION STUDIES ACROSS MAJOR PSYCHIATRIC DISORDERS IN EUR, AFR/AFAM, AND ASN/ASAM POPULATIONS

IF 6.1 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology Pub Date : 2024-10-01 DOI:10.1016/j.euroneuro.2024.08.070

Omar Shanta , Worrawat Engchuan , Jeff MacDonald , Marieke Klein , Bhooma Thiruvahindrapuram , Adam Maihofer , Molly Sacks , Mohammad Ahangari , Sebastien Jacquemont , Kimberley Kendall , Ida Sonderby , Guillaume Huguet , Steven H. Scherer , Jonathan Sebat , The Bipolar Disorder, Schizophrenia, Post-Traumatic Stress Disorder, Attention-Deficit/Hyperactivity Disorder, Major Depressive Disorder, Autism Spectrum Disorder and Copy Number Variation Working groups of the Psychiatric Genomics Consortium

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引用次数: 0

Abstract

Genome-wide association studies (GWAS) to date have been able to leverage large sample sizes to identify genomic loci that contribute to risk for various psychiatric disorders. However, GWAS of copy number variants (CNVs) have prioritized identifying risk loci within European populations due to the lack of power in diverse ancestry groups. In this study, we called CNVs in a diverse group of samples to create CNV datasets for 2 additional ancestry groups: African/African American (AFR/AFAM) and Asian/Asian American (ASN/ASAM). SNPweights was used to infer genome-wide genetic ancestry for each sample. We were then able to boost power at specific loci by using a meta-analysis to combine EUR, AFR/AFAM, and ASN/ASAM CNV analyses (N=571,803).

Rare copy number variants have been implicated in a cross-disorder European cohort (N=537,466) that includes major psychiatric disorders such as autism (ASD), schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD), and attention-deficit/hyperactivity disorder (ADHD). This analysis was able to identify novel loci with the statistical power that comes with being the largest CNV study to date. Naturally, the inclusion of diverse samples in this analysis can further lead to novel discoveries. Additional CNV-GWAS were performed for cross-disorder datasets in AFR/AFAM (N=17,474) and ASN/ASAM (N=16,863) populations. Meta-analysis of all 3 populations used an inverse-variance weighting to account for the disparity of sample size between populations. We compared EUR CNV-GWAS and burden results with those from the meta-analysis as these were the most well-powered tests. The effect was a substantial increase in significance levels at specific loci that reached testable CNV frequencies in the diverse groups. Comparing the EUR analysis with the trans-ancestry analysis allows us to quantify the contribution of the diverse groups and provide insight into the genomic loci associated with psychiatric disorders in AFR/AFAM and ASN/ASAM populations once similar sample sizes are reached. This study highlights the importance of expanding diversity during data collection so that the genotype-phenotype relationships can benefit people worldwide.

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对欧洲、非洲/非洲医学会和亚洲医学会/亚洲医学会人群中主要精神疾病的罕见 CNV 全基因组关联研究的荟萃分析

迄今为止，全基因组关联研究（GWAS）能够利用大样本量来确定导致各种精神疾病风险的基因组位点。然而，拷贝数变异（CNVs）的全基因组关联研究由于缺乏对不同祖先群体的研究，一直优先考虑确定欧洲人群中的风险位点。在这项研究中，我们调用了一组不同样本中的 CNVs，为另外两个祖先群体创建了 CNV 数据集：非洲/非裔美国人（AFR/AFAM）和亚洲/亚裔美国人（ASN/ASAM）。SNPweights 用于推断每个样本的全基因组遗传祖先。然后，我们利用荟萃分析将欧洲人、非洲裔美国人/非洲裔美国人和亚裔美国人/亚裔美国人的 CNV 分析结合起来（N=571,803），从而提高了特定位点的分析能力。罕见拷贝数变异已牵涉到一个跨障碍的欧洲队列（N=537,466），其中包括自闭症（ASD）、精神分裂症（SCZ）、重度抑郁障碍（MDD）、双相情感障碍（BD）、创伤后应激障碍（PTSD）和注意力缺陷/多动障碍（ADHD）等主要精神障碍。这项分析能够发现新的基因座，其统计能力是迄今为止最大的 CNV 研究所具备的。当然，将不同的样本纳入这项分析还能进一步带来新的发现。我们还对AFR/AFAM（样本数=17,474）和ASN/ASAM（样本数=16,863）人群的交叉紊乱数据集进行了CNV-GWAS分析。对所有 3 个人群的 Meta 分析都采用了反方差加权法，以考虑不同人群样本量的差异。我们将 EUR CNV-GWAS 和负担结果与荟萃分析的结果进行了比较，因为这些是最有效的检测方法。结果显示，在不同群体中，达到可检测 CNV 频率的特定位点的显著性水平大幅提高。将EUR分析与跨种群分析进行比较，可以量化不同群体的贡献，并在样本量达到类似规模后，深入了解与AFR/AFAM和ASN/ASAM人群精神障碍相关的基因组位点。这项研究强调了在数据收集过程中扩大多样性的重要性，从而使基因型与表型之间的关系造福于全世界的人们。

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来源期刊

European Neuropsychopharmacology 医学-精神病学

CiteScore

10.30

自引率

5.40%

发文量

730

审稿时长

41 days

期刊介绍： European Neuropsychopharmacology is the official publication of the European College of Neuropsychopharmacology (ECNP). In accordance with the mission of the College, the journal focuses on clinical and basic science contributions that advance our understanding of brain function and human behaviour and enable translation into improved treatments and enhanced public health impact in psychiatry. Recent years have been characterized by exciting advances in basic knowledge and available experimental techniques in neuroscience and genomics. However, clinical translation of these findings has not been as rapid. The journal aims to narrow this gap by promoting findings that are expected to have a major impact on both our understanding of the biological bases of mental disorders and the development and improvement of treatments, ideally paving the way for prevention and recovery.