Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Schizophr Bull. 2024 Aug 27;50(5):1255-1265. doi: 10.1093/schbul/sbae087.
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.
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.
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.
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.
精神分裂症（SCZ）和神经性厌食症（AN）是两种严重且高度异质的疾病，具有显著的家族聚集性。遗传因素在这两种疾病中都起着重要作用，但它们之间的共同遗传病因尚未得到研究。
利用最近关于 SCZ（Ncases=53386）和 AN（Ncases=16992）的大型全基因组关联研究的汇总统计数据，进行了两样本 Mendelian 随机化分析，以探讨 SCZ 和 AN 之间的因果关系。MiXeR 用于量化它们的多基因重叠。采用条件/联合假发现率（condFDR/conjFDR）框架来识别与两种疾病都相关的位点。对共享位点进行功能注释和富集分析。
我们观察到 SCZ 和 AN 之间存在跨表型遗传富集、提示性双向因果关系和相当大的多基因重叠（Dice 系数=62.2%）。所有共享变异中具有一致效应方向的变异比例为 69.9%。利用重叠的遗传关联，我们在 condFDR<0.01 水平下确定了 6 个新的 AN 位点和 33 个新的 SCZ 位点；在 conjFDR<0.05 水平下，我们确定了 10 个与两种疾病都相关的位点，涉及多个在小脑和垂体中高度表达并参与突触组织的基因。特别是，在青春期的海马体和婴儿期的眶额皮层中观察到共享基因的高表达。
本研究通过揭示共同的遗传成分，为 SCZ 和 AN 之间的关系提供了新的见解，并为它们的复杂病因提供了一个窗口。
