Genome-wide association study of cerebellar white matter microstructure and genetic overlap with common brain disorders
Bang-Sheng Wu,
Yi-Jun Ge,
Wei Zhang,
Shi-Dong Chen,
Shi-Tong Xiang,
Ya-Ru Zhang,
Ya-Nan Ou,
Yu-Chao Jiang,
Lan Tan,
Wei Cheng,
John Suckling,
Jian-Feng Feng,
Jin-Tai Yu,
Ying Mao
Affiliations
Bang-Sheng Wu
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
Yi-Jun Ge
Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
Wei Zhang
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China
Shi-Dong Chen
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
Shi-Tong Xiang
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China
Ya-Ru Zhang
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
Ya-Nan Ou
Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
Yu-Chao Jiang
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China
Lan Tan
Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
Wei Cheng
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China; Fudan ISTBI—ZJNU Algorithm Centre for Brain-Inspired Intelligence, Zhejiang Normal University, Jinhua, China; Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
John Suckling
Department of Psychiatry, Brain Mapping Unit, University of Cambridge, Cambridge, CB2 0SZ, UK
Jian-Feng Feng
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China; Department of Computer Science, University of Warwick, Coventry CV4 7AL, UK
Jin-Tai Yu
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China; Corresponding authors at: Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai 200040, China.
Ying Mao
Department of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China; Corresponding authors at: Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai 200040, China.
Background: The cerebellum is recognized as being involved in neurocognitive and motor functions with communication with extra-cerebellar regions relying on the white matter integrity of the cerebellar peduncles. However, the genetic determinants of cerebellar white matter integrity remain largely unknown. Methods: We conducted a genome-wide association analysis of cerebellar white matter microstructure using diffusion tensor imaging data from 25,415 individuals from UK Biobank. The integrity of cerebellar white matter microstructure was measured as fractional anisotropy (FA) and mean diffusivity (MD). Identification of independent genomic loci, functional annotation, and tissue and cell-type analysis were conducted with FUMA. The linkage disequilibrium score regression (LDSC) was used to calculate genetic correlations between cerebellar white matter microstructure and regional brain volumes and brain-related traits. Furthermore, the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was employed to identify the shared genetic basis between cerebellar white matter microstructure and common brain disorders. Results: We identified 11 genetic loci (P < 8.3 × 10−9) and 86 genes associated with cerebellar white matter microstructure. Further functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. Significant polygenetic overlap between cerebellar white matter tracts and their anatomically connected or adjacent brain regions was detected. In addition, we report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits, including movement, cognitive, psychiatric, and cerebrovascular categories. Conclusions: Collectively, this study represents a step forward in understanding the genetics of cerebellar white matter microstructure and its shared genetic etiology with common brain disorders.
