Genome‐Wide by Lifetime Environment Interaction Studies of Brain Imaging Phenotypes

Brain structure and function show substantial individual differences, finely controlled by genes, environments, and their interactions. Despite the increasing knowledge about genetic and environmental main effects, gene-environment interaction effects on brain phenotypes remain elusive. This study investigates genome-wide by environment (41 exposures) interactions on 598 brain imaging phenotypes in 7084 healthy young adults. Both univariate and multivariate analyses identify 486 significant gene-environment interactions, scattered across the genome, exposome, and phenome. These interactions explain more variances of phenotypes than genetic and environmental main effects (100% of genetic and 96% of environmental main effects are non-significant). Variants with interactions are enriched in intronic and intergenic regions, comprising 79 regulatory variants and 145 associated with brain gene expression. Protein-protein interaction network analyses reveal distinct interaction networks for genes associated with air pollution (hubs: H4C6, SMARCA4, and RPS11) and urbanicity (hubs: CCND1, CALM3, and CDK2) exposures. Genes that interacted with air pollution exposures exhibit enrichment in pathways related to metal ion detoxification and homeostasis. For time-varying exposures, 144 interactions demonstrate sensitive periods, predominantly in childhood (ages 4-7) and adolescence (ages 12-15). These findings highlight the value of genome-wide by exposome-wide interaction studies, which may offer crucial information for optimizing brain health outcomes.

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Publication Details

Journal
Advanced Science
Published
2025-11-29
DOI
https://doi.org/10.1002/advs.202500852
Primary Topic
Health, Environment, Cognitive Aging
Type
article
Field-Weighted Citation Impact
0.00

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article

Genome‐Wide by Lifetime Environment Interaction Studies of Brain Imaging Phenotypes

Jia‐Hong Gao, Junfang Xian, Su Lui, Jiayuan Xu et al.
Advanced Science
Health, Environment, Cognitive Aging
article

Genome‐Wide by Lifetime Environment Interaction Studies of Brain Imaging Phenotypes

Jia‐Hong Gao, Junfang Xian, Su Lui, Jiayuan Xu, Jie Tang, Qiang Xu, Mengge Liu, Zhenwei Yao, Long Jiang Zhang, Xi‐Nian Zuo, Yongqiang Yu, Guangbin Cui, Wenzhen Zhu, Wen Shen, Jingliang Cheng, Yuan Ji, Caihong Wang, Meng Liang, Kai Xu, Bing Zhang, Chunshui Yu, Wen Xin QIN, Bo Gao, Xiaochu Zhang, Zuojun Geng, Wei Li, Xiaojun Xu, Zhihan Yan, Zhaoxiang Ye, Xiaoxiao Xiao, Hui Zhang, Wei Wei, Jing Zhang, Feng Chen, Peng Zhang, Quan Zhang, Feng Liu, Dawei Wang, Nana Liu, Xiaoxuan Liu, Meiyun Wang, Le Yu, Jilian Fu, Yanwei Miao, Dapeng Shi, Weihua Liao, Lining Guo, Shijun Qiu, Sijia Wang, Tong Han, Yunjun Yang
article en

Abstract

Brain structure and function show substantial individual differences, finely controlled by genes, environments, and their interactions. Despite the increasing knowledge about genetic and environmental main effects, gene-environment interaction effects on brain phenotypes remain elusive. This study investigates genome-wide by environment (41 exposures) interactions on 598 brain imaging phenotypes in 7084 healthy young adults. Both univariate and multivariate analyses identify 486 significant gene-environment interactions, scattered across the genome, exposome, and phenome. These interactions explain more variances of phenotypes than genetic and environmental main effects (100% of genetic and 96% of environmental main effects are non-significant). Variants with interactions are enriched in intronic and intergenic regions, comprising 79 regulatory variants and 145 associated with brain gene expression. Protein-protein interaction network analyses reveal distinct interaction networks for genes associated with air pollution (hubs: H4C6, SMARCA4, and RPS11) and urbanicity (hubs: CCND1, CALM3, and CDK2) exposures. Genes that interacted with air pollution exposures exhibit enrichment in pathways related to metal ion detoxification and homeostasis. For time-varying exposures, 144 interactions demonstrate sensitive periods, predominantly in childhood (ages 4-7) and adolescence (ages 12-15). These findings highlight the value of genome-wide by exposome-wide interaction studies, which may offer crucial information for optimizing brain health outcomes.

Advanced ScienceVol. 13(8)
Hebei Medical University (CN), University of Science and Technology of China (CN), Beijing Tongren Hospital (CN), Central South University (CN), McGovern Institute for Brain Research (US), Guiyang Medical University (CN), Shanxi Medical University (CN), Xuzhou Medical College (CN), Capital Medical University (CN), Dalian Medical University (CN), Anhui Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Sichuan University (CN), Fudan University (CN), Beijing Normal University (CN), Wenzhou Medical University (CN), Nanjing General Hospital of Nanjing Military Command (CN), Tianjin First Center Hospital (CN), First Affiliated Hospital of Wenzhou Medical University (CN), Tianjin Medical University General Hospital (CN), Tianjin Medical University Cancer Institute and Hospital (CN), Yuhuangding Hospital (CN), Zhengzhou University (CN), Chinese People's Armed Police Force Medical College Affiliated Hospital (CN), West China Hospital of Sichuan University (CN), Henan Academy of Sciences (CN), Second Hospital of Hebei Medical University (CN), Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University (CN), Tianjin Huanhu Hospital (CN), First Affiliated Hospital of Guangzhou University of Chinese Medicine (CN), Affiliated Hospital of Xuzhou Medical College (CN), Affiliated Hospital of Guizhou Medical University (CN), Ministry of Education (ME), Nanjing Drum Tower Hospital (CN), Chinese Institute for Brain Research (CN), Chinese People's Armed Police General Hospital (CN), Lanzhou University Second Hospital (CN), First Hospital of Shanxi Medical University (CN), Hainan General Hospital (CN), Institute of Psychology, Chinese Academy of Sciences (CN), Henan Provincial People's Hospital (CN), First Affiliated Hospital of Anhui Medical University (CN), Second Affiliated Hospital of Nanjing Medical University (CN), First Affiliated Hospital of Dalian Medical University (CN), Tang Du Hospital (CN), First Affiliated Hospital of Zhengzhou University (CN), Second Affiliated Hospital of Zhejiang University (CN), Huashan Hospital (CN), Xiangya Hospital Central South University (CN), Institute of Physics (CN), Tongji Hospital (CN), Center for Life Sciences (CN), Qilu Hospital of Shandong University (CN), Gansu Provincial Center for Disease Control and Prevention (CN), Chinese People's Armed Police Force, Huazhong University of Science and Technology (CN), Tianjin Medical University (CN), Lanzhou University (CN), Hainan Medical University (CN), Nanjing Medical University (CN), Nanjing University (CN), Tsinghua University (CN), Air Force Medical University (CN)
National Natural Science Foundation of China, China Postdoctoral Science Foundation
Openalex Percentile: Top 53%
Health, Environment, Cognitive Aging
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