CHARACTERIZATION OF A SUICIDAL BEHAVIOR GWAS LOCUS ON CHROMOSOME 7

IF 6.1 2区医学 Q1 CLINICAL NEUROLOGY European Neuropsychopharmacology Pub Date : 2024-10-01 DOI:10.1016/j.euroneuro.2024.08.050

Laura Fiori, Anjali Chawla, Corina Nagy, Gustavo Turecki

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Abstract

Suicide is one of the leading causes of death worldwide. Although suicidal behaviors demonstrate high heritability, identifying the genetic factors underlying these behaviors has been challenging. A recent genome-wide association study for suicide and suicide attempt identified an intergenic SNP on chromosome 7, rs62474683, which was significantly associated with suicide attempt, independently of psychiatric disorders.

In order to determine the potential functional effects of rs62474683 genotype, and how it may be related to suicide, we ascertained expression of genes within a 1.8Mbp region surrounding this SNP in two different brain regions and investigated the relationship between genetic variation and gene expression. Additionally, we explored, at the single cell level, the effect of the variant on gene expression and chromatin accessibility.

We found differential expression of Forkhead box P2 (FOXP2), transcription factor EC (TFEC), and Testin LIM domain protein (TES) in the brains of individuals who died by suicide and found that FOXP2 and MyoD family inhibitor domain containing (MDFIC) expression was related to rs62474683. Additionally, the relationship between FOXP2 expression and suicide appeared to be both brain region- and cell type-specific. Finally, we found evidence for direct relationships between the region containing rs62474683 and FOXP2, MDFIC, and TES.

Our study provides evidence for a functional relationship between the most significant suicide attempt loci to date and genes displaying differential expression related to suicide.

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7 号染色体上自杀行为 gwas 基因座的特征

自杀是导致全球死亡的主要原因之一。虽然自杀行为具有很高的遗传性，但确定这些行为背后的遗传因素一直是一项挑战。为了确定 rs62474683 基因型的潜在功能影响以及它与自杀的关系，我们在两个不同的脑区确定了围绕该 SNP 的 1.8Mbp 区域内基因的表达，并研究了遗传变异与基因表达之间的关系。此外，我们还在单细胞水平上探讨了该变异对基因表达和染色质可及性的影响。我们发现自杀死亡者大脑中叉头盒 P2（FOXP2）、转录因子 EC（TFEC）和睾丸素 LIM 结构域蛋白（TES）的表达存在差异，并发现 FOXP2 和 MyoD 家族抑制剂结构域（MDFIC）的表达与 rs62474683 有关。此外，FOXP2 表达与自杀之间的关系似乎具有大脑区域和细胞类型特异性。最后，我们发现了含有 rs62474683 的区域与 FOXP2、MDFIC 和 TES 之间存在直接关系的证据。我们的研究为迄今为止最重要的自杀未遂基因座与自杀相关差异表达基因之间的功能关系提供了证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.