Whole-exome sequencing identifies protein-coding variants associated with brain iron in 29,828 individuals

• Published in: Nature communications Vol. 15; no. 1; pp. 5540 - 13
• Main Authors: Gong, Weikang, Fu, Yan, Wu, Bang-Sheng, Du, Jingnan, Yang, Liu, Zhang, Ya-Ru, Chen, Shi-Dong, Kang, JuJiao, Mao, Ying, Dong, Qiang, Tan, Lan, Feng, Jianfeng, Cheng, Wei, Yu, Jin-Tai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 49; 59/57; 631/208/205; 631/378/1689; 631/378/2583; Accumulation; Adult; Aged; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Association analysis; Biobanks; Brain; Brain - metabolism; Brain architecture; Brain mapping; Disorders; Exome Sequencing; Female; Gene mapping; Genes; Genetic analysis; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Genomes; Glial fibrillary acidic protein; Homeostasis; Humanities and Social Sciences; Humans; Iron; Iron - metabolism; Magnetic resonance imaging; Male; Medical imaging; Mendelian Randomization Analysis; Mental disorders; Middle Aged; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural coding; Neuroimaging; Neurosciences; Parkinson Disease - genetics; Parkinson Disease - metabolism; Peptide mapping; Proteins; Science; Science (multidisciplinary); Substantia nigra; Therapeutic targets; Whole genome sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49702-2

Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX . Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson’s ( STAB1 , KCNA10 ), Alzheimer’s ( SHANK1 ), and depression ( GFAP ). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson’s. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders. Brain iron accumulation has been associated with multiple brain disorders, but the mechanism is not well understood. Here, the authors investigate the genetic determinants of brain iron accumulation and their implications for neuropsychiatric disorders.