精神分裂症与神经性厌食症的共同遗传结构:全基因组跨性状分析

IF 5.3 1区 医学 Q1 PSYCHIATRY Schizophrenia Bulletin Pub Date : 2024-08-27 DOI:10.1093/schbul/sbae087
Zheng-An Lu, Alexander Ploner, Andreas Birgegård, Cynthia M Bulik, Sarah E Bergen
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引用次数: 0

摘要

背景和假设:精神分裂症(SCZ)和神经性厌食症(AN)是两种严重且高度异质性的疾病,具有大量的家族聚集性。遗传因素在这两种疾病中起着重要作用,但它们之间的共同遗传病因仍有待研究:研究设计:利用最近对SCZ(Ncases = 53 386)和AN(Ncases = 16 992)进行的大型全基因组关联研究的汇总统计数据,进行了双样本孟德尔随机分析,以探讨SCZ和AN之间的因果关系。MiXeR 被用来量化它们的多基因重叠。采用条件/联合错误发现率(condFDR/conjFDR)框架来确定与这两种疾病共同相关的位点。研究结果:我们观察到SCZ和AN之间存在跨性状遗传富集、提示性双向因果关系和相当大的多基因重叠(Dice系数=62.2%)。在所有共有变异中,效应方向一致的变异比例为69.9%。利用重叠的遗传关联,我们在condFDR结论中发现了6个新的AN基因位点和33个新的SCZ基因位点:这项研究揭示了SCZ和AN之间的共同遗传因素,为了解它们之间的关系提供了新的视角,也为了解它们复杂的病因学提供了一个窗口。
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Shared Genetic Architecture Between Schizophrenia and Anorexia Nervosa: A Cross-trait Genome-Wide Analysis.

Background and hypothesis: Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated.

Study design: Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci.

Study results: We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy.

Conclusions: This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.

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来源期刊
Schizophrenia Bulletin
Schizophrenia Bulletin 医学-精神病学
CiteScore
11.40
自引率
6.10%
发文量
163
审稿时长
4-8 weeks
期刊介绍: Schizophrenia Bulletin seeks to review recent developments and empirically based hypotheses regarding the etiology and treatment of schizophrenia. We view the field as broad and deep, and will publish new knowledge ranging from the molecular basis to social and cultural factors. We will give new emphasis to translational reports which simultaneously highlight basic neurobiological mechanisms and clinical manifestations. Some of the Bulletin content is invited as special features or manuscripts organized as a theme by special guest editors. Most pages of the Bulletin are devoted to unsolicited manuscripts of high quality that report original data or where we can provide a special venue for a major study or workshop report. Supplement issues are sometimes provided for manuscripts reporting from a recent conference.
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