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

doi:10.1016/j.celrep.2023.112896

Chromosomal inversion polymorphisms shape human brain morphology

Cell Rep. 2023 Aug 29;42(8):112896. doi: 10.1016/j.celrep.2023.112896. Epub 2023 Jul 27.

Authors

Hao Wang¹, Carolina Makowski¹, Yanxiao Zhang², Anna Qi¹, Tobias Kaufmann³, Olav B Smeland⁴, Mark Fiecas⁵, Jian Yang⁶, Peter M Visscher⁷, Chi-Hua Chen⁸

Affiliations

¹ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA.
² 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.
³ 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.
⁴ Norwegian Centre for Mental Disorders Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway.
⁵ Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA.
⁶ School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
⁷ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
⁸ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: chc101@ucsd.edu.

Abstract

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.

Keywords: CP: Genomics; CP: Neuroscience; brain morphology; gene regulation; inversion polymorphism; magnetic resonance imaging; molecular QTL; neurodevelopment; segmental duplication; structural variant.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Brain
Child
Chromosome Inversion* / genetics
Humans
Polymorphism, Genetic*

Abstract

Publication types

MeSH terms

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