Chromosomal inversion polymorphisms shape human brain morphology
Hao Wang,
Carolina Makowski,
Yanxiao Zhang,
Anna Qi,
Tobias Kaufmann,
Olav B. Smeland,
Mark Fiecas,
Jian Yang,
Peter M. Visscher,
Chi-Hua Chen
Affiliations
Hao Wang
Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA
Carolina Makowski
Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA
Yanxiao Zhang
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China
Anna Qi
Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA
Tobias Kaufmann
Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, 72076 Tübingen, Germany; Norwegian Centre for Mental Disorders Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway
Olav B. Smeland
Norwegian Centre for Mental Disorders Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway
Mark Fiecas
Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA
Jian Yang
School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China
Peter M. Visscher
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
Chi-Hua Chen
Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA; Corresponding author
Summary: The impact of chromosomal inversions on human brain morphology remains underexplored. We studied 35 common inversions classified from genotypes of 33,018 adults with European ancestry. The inversions at 2p22.3, 16p11.2, and 17q21.31 reach genome-wide significance, followed by 8p23.1 and 6p21.33, in their association with cortical and subcortical morphology. The 17q21.31, 8p23.1, and 16p11.2 regions comprise the LRRC37, OR7E, and NPIP duplicated gene families. We find the 17q21.31 MAPT inversion region, known for harboring neurological risk, to be the most salient locus among common variants for shaping and patterning the cortex. Overall, we observe the inverted orientations decreasing brain size, with the exception that the 2p22.3 inversion is associated with increased subcortical volume and the 8p23.1 inversion is associated with increased motor cortex. These significant inversions are in the genomic hotspots of neuropsychiatric loci. Our findings are generalizable to 3,472 children and demonstrate inversions as essential genetic variation to understand human brain phenotypes.
