journal article·2026-02Open access

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

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

Advanced Science· Volume 13· Issue 8

Abstract

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.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Health, Environment, Cognitive Aging · Functional Brain Connectivity Studies · Genetic Associations and Epidemiology

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Radiology Tianjin Key Lab of Functional Imaging and State Key Laboratory of Experimental Hematology Tianjin Medical University General Hospital Tianjin 300052 China

Department of Radiology Henan Provincial People's Hospital & Zhengzhou University People's Hospital Zhengzhou 450003 China

Biomedical Institute Henan Academy of Sciences Zhengzhou 450199 China

Department of Radiology Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer Tianjin's Clinical Research Center for Cancer Tianjin Medical University Ministry of Education Key Laboratory of Cancer Prevention and Therapy Tianjin 300060 China

Department of Magnetic Resonance Imaging The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 China

Department of Radiology Jinling Hospital, Affiliated Hospital of Medical School Nanjing University Nanjing 210002 China

Department of Radiology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China

Department of Medical Imaging The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine Guangzhou 510405 China

Department of Medical Imaging The Second Hospital of Hebei Medical University Shijiazhuang 050000 China

Functional and Molecular Imaging Key Lab of Shaanxi Province & Department of Radiology Tangdu Hospital Air Force Medical University Xi'an 710038 China

Department of Radiology The First Affiliated Hospital of Anhui Medical University Hefei 230022 China

Department of Radiology Xiangya Hospital Central South University Changsha 410008 China

Molecular Imaging Research Center of Central South University Changsha 410008 China

National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha 410008 China

Developmental Population Neuroscience Research Center at IDG/McGovern Institute for Brain Research Beijing Normal University Beijing 100875 China

Institute of Psychology Chinese Academy of Sciences Beijing 100101 China

Department of Radiology The First Hospital of Shanxi Medical University Taiyuan 030001 China

Department of Radiology The Affiliated Hospital of Guizhou Medical University Guiyang 550004 China

Department of Radiology Yantai Yuhuangding Hospital Yantai 264000 China

Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310009 China

Department of Radiology Tianjin Huanhu Hospital Tianjin 300350 China

Department of Radiology Huashan Hospital Fudan University Shanghai 200040 China

Department of Radiology Characteristic Medical Center of Chinese People's Armed Police Force Tianjin 300162 China

School of Medical Imaging (School of Medical Technology) and Tianjin Key Laboratory of Functional Imaging Tianjin Medical University Tianjin 300203 China

Ministry of Education Key Laboratory for Earth System Modeling Department of Earth System Science Tsinghua University Beijing 100084 China

Funding

National Natural Science Foundation of China · China Postdoctoral Science Foundation · National Key Research and Development Program of China

References (100+)

Show source-provided references
1. 10.1038/nn.413510.1038/nn.4135 ↗
2. 10.1016/j.neuron.2012.12.02810.1016/j.neuron.2012.12.028 ↗
3. 10.1016/j.tics.2013.02.00310.1016/j.tics.2013.02.003 ↗
4. 10.1093/cercor/bhab10910.1093/cercor/bhab109 ↗
5. 10.1038/s41583-022-00584-710.1038/s41583-022-00584-7 ↗
6. 10.1186/s12916-019-1488-110.1186/s12916-019-1488-1 ↗
7. 10.1016/S1474-4422(18)30451-410.1016/S1474-4422(18)30451-4 ↗
8. 10.1186/s12916-023-02963-y10.1186/s12916-023-02963-y ↗
9. 10.1073/pnas.190039011610.1073/pnas.1900390116 ↗
10. 10.1038/s41586-018-0571-710.1038/s41586-018-0571-7 ↗
11. 10.1038/nn75810.1038/nn758 ↗
12. 10.1073/pnas.112125410910.1073/pnas.1121254109 ↗
13. 10.1038/s41380-022-01669-610.1038/s41380-022-01669-6 ↗
14. 10.2174/157340505403872610.2174/1573405054038726 ↗
15. 10.1016/j.neuroimage.2009.12.02810.1016/j.neuroimage.2009.12.028 ↗
16. 10.1016/j.neuroimage.2017.12.09710.1016/j.neuroimage.2017.12.097 ↗
17. 10.1038/s41588-022-01039-610.1038/s41588-022-01039-6 ↗
18. 10.1177/107385841559500410.1177/1073858415595004 ↗
19. 10.1038/s41593-021-00826-410.1038/s41593-021-00826-4 ↗
20. 10.1126/science.abf373610.1126/science.abf3736 ↗
21. 10.1126/science.aay669010.1126/science.aay6690 ↗
22. 10.1126/science.abe845710.1126/science.abe8457 ↗
23. 10.1016/j.biopsych.2018.01.01610.1016/j.biopsych.2018.01.016 ↗
24. 10.1038/s41562-021-01204-710.1038/s41562-021-01204-7 ↗
25. 10.1038/s41593-019-0451-y10.1038/s41593-019-0451-y ↗
26. 10.1038/nn.398310.1038/nn.3983 ↗
27. 10.1073/pnas.190080111610.1073/pnas.1900801116 ↗
28. 10.1038/s41467-019-08500-x10.1038/s41467-019-08500-x ↗
29. 10.1073/pnas.140835511110.1073/pnas.1408355111 ↗
30. 10.1002/hipo.2077510.1002/hipo.20775 ↗
31. 10.1371/journal.pone.015575510.1371/journal.pone.0155755 ↗
32. 10.1016/j.neuroimage.2016.04.00910.1016/j.neuroimage.2016.04.009 ↗
33. 10.1016/j.jad.2015.09.03110.1016/j.jad.2015.09.031 ↗
34. 10.1038/s41380-019-0627-610.1038/s41380-019-0627-6 ↗
35. 10.1038/s41588-018-0271-010.1038/s41588-018-0271-0 ↗
36. 10.1186/s13742-015-0047-810.1186/s13742-015-0047-8 ↗
37. 10.1111/j.0006-341X.1999.00997.x10.1111/j.0006-341X.1999.00997.x ↗
38. 10.1126/sciadv.adp375110.1126/sciadv.adp3751 ↗
39. 10.1038/s41467-017-01261-510.1038/s41467-017-01261-5 ↗
40. 10.1093/nar/gkq60310.1093/nar/gkq603 ↗
41. 10.1038/ng.289210.1038/ng.2892 ↗
42. 10.1101/gr.137323.11210.1101/gr.137323.112 ↗
43. 10.1038/s41588-021-00987-910.1038/s41588-021-00987-9 ↗
44. 10.1212/NXG.000000000000059310.1212/NXG.0000000000000593 ↗
45. 10.1007/s12311-023-01606-510.1007/s12311-023-01606-5 ↗
46. 10.1371/journal.pcbi.100421910.1371/journal.pcbi.1004219 ↗
47. 10.1093/nar/gkac100010.1093/nar/gkac1000 ↗
48. 10.1038/s41593-023-01414-410.1038/s41593-023-01414-4 ↗
49. 10.1002/syn.2184010.1002/syn.21840 ↗
50. 10.1016/j.cellsig.2020.10959210.1016/j.cellsig.2020.109592 ↗
51. 10.1038/sj.tpj.650008510.1038/sj.tpj.6500085 ↗
52. 10.1146/annurev-psych-010213-11510010.1146/annurev-psych-010213-115100 ↗
53. 10.18637/jss.v043.i0810.18637/jss.v043.i08 ↗
54. 10.1038/s41588-024-01908-210.1038/s41588-024-01908-2 ↗
55. 10.1038/s41398-021-01272-310.1038/s41398-021-01272-3 ↗
56. 10.1038/s41586-024-08468-910.1038/s41586-024-08468-9 ↗
57. 10.1001/jamapsychiatry.2021.209910.1001/jamapsychiatry.2021.2099 ↗
58. 10.1001/jamaneurol.2020.042810.1001/jamaneurol.2020.0428 ↗
59. 10.1038/s41586-022-04434-510.1038/s41586-022-04434-5 ↗
60. 10.1038/s41586-022-05165-310.1038/s41586-022-05165-3 ↗
61. 10.1038/s41467-019-09718-510.1038/s41467-019-09718-5 ↗
62. 10.12688/f1000research.21933.110.12688/f1000research.21933.1 ↗
63. 10.1038/s41388-023-02773-910.1038/s41388-023-02773-9 ↗
64. 10.1038/nn.459810.1038/nn.4598 ↗
65. 10.1016/j.ajhg.2022.02.00310.1016/j.ajhg.2022.02.003 ↗
66. 10.1016/j.compbiolchem.2018.12.01110.1016/j.compbiolchem.2018.12.011 ↗
67. 10.3389/fphar.2021.80698410.3389/fphar.2021.806984 ↗
68. 10.1016/j.phymed.2023.15521510.1016/j.phymed.2023.155215 ↗
69. 10.3390/cells1006141010.3390/cells10061410 ↗
70. 10.1007/s12640-011-9287-210.1007/s12640-011-9287-2 ↗
71. 10.1016/j.neuro.2007.12.00610.1016/j.neuro.2007.12.006 ↗
72. 10.1016/B978-0-12-823292-7.00004-810.1016/B978-0-12-823292-7.00004-8 ↗
73. 10.1038/s41467-018-03126-x10.1038/s41467-018-03126-x ↗
74. 10.1113/JP27049210.1113/JP270492 ↗
75. 10.1002/bdr2.117810.1002/bdr2.1178 ↗
76. 10.1038/nrn.2018.1010.1038/nrn.2018.10 ↗
77. 10.12688/f1000research.23216.110.12688/f1000research.23216.1 ↗
78. 10.1016/j.envint.2019.10521210.1016/j.envint.2019.105212 ↗
79. 10.1016/j.tics.2015.07.00810.1016/j.tics.2015.07.008 ↗
80. 10.1007/s11065-012-9214-110.1007/s11065-012-9214-1 ↗
81. 10.1038/1315810.1038/13158 ↗
82. 10.1016/j.neuron.2014.07.04010.1016/j.neuron.2014.07.040 ↗
83. 10.1038/s41386-021-01137-910.1038/s41386-021-01137-9 ↗
84. 10.1038/tp.2013.710.1038/tp.2013.7 ↗
85. Konrad K. · Deutsches Arzteblatt Int. · 2013 · 110 · 425
86. 10.1017/S095457942100183810.1017/S0954579421001838 ↗
87. 10.1001/jamapediatrics.2023.400310.1001/jamapediatrics.2023.4003 ↗
88. 10.1016/S0140-6736(15)00238-X10.1016/S0140-6736(15)00238-X ↗
89. 10.1016/S0140-6736(09)60995-810.1016/S0140-6736(09)60995-8 ↗
90. 10.1097/01.chi.0000223313.25536.4710.1097/01.chi.0000223313.25536.47 ↗
91. 10.1016/S0140-6736(23)02238-910.1016/S0140-6736(23)02238-9 ↗
92. 10.1097/YCO.000000000000048610.1097/YCO.0000000000000486 ↗
93. 10.1155/2024/667352210.1155/2024/6673522 ↗
94. 10.1016/j.biopsych.2012.04.02010.1016/j.biopsych.2012.04.020 ↗
95. Hoogman M. · Psychiatry · 2017 · 4 · 310
96. 10.1016/j.psychres.2022.11504510.1016/j.psychres.2022.115045 ↗
97. 10.1016/S0140-6736(16)30066-610.1016/S0140-6736(16)30066-6 ↗
98. 10.1038/s41586-018-0579-z10.1038/s41586-018-0579-z ↗
99. 10.1111/jora.1237410.1111/jora.12374 ↗
100. 10.1038/s41588-024-01766-y10.1038/s41588-024-01766-y ↗