Detection and analysis of complex structural variation in human genomes across populations and in brains of donors with psychiatric disorders

Bo Zhou; Joseph G Arthur; Hanmin Guo; Taeyoung Kim; Yiling Huang; Reenal Pattni; Tao Wang; Soumya Kundu; Jay X J Luo; HoJoon Lee; Daniel C Nachun; Carolin Purmann; Emma M Monte; Annika K Weimer; Ping-Ping Qu; Minyi Shi; Lixia Jiang; Xinqiong Yang; John F Fullard; Jaroslav Bendl; Kiran Girdhar; Minsu Kim; Xi Chen; PsychENCODE Consortium; William J Greenleaf; Laramie Duncan; Hanlee P Ji; Xiang Zhu; Giltae Song; Stephen B Montgomery; Dean Palejev; Heinrich Zu Dohna; Panos Roussos; Anshul Kundaje; Joachim F Hallmayer; Michael P Snyder; Wing H Wong; Alexander E Urban

doi:10.1016/j.cell.2024.09.014

Detection and analysis of complex structural variation in human genomes across populations and in brains of donors with psychiatric disorders

Cell. 2024 Nov 14;187(23):6687-6706.e25. doi: 10.1016/j.cell.2024.09.014. Epub 2024 Sep 30.

Authors

Bo Zhou¹, Joseph G Arthur², Hanmin Guo³, Taeyoung Kim⁴, Yiling Huang⁵, Reenal Pattni⁵, Tao Wang⁶, Soumya Kundu⁷, Jay X J Luo⁶, HoJoon Lee⁸, Daniel C Nachun⁹, Carolin Purmann¹⁰, Emma M Monte⁶, Annika K Weimer⁶, Ping-Ping Qu⁵, Minyi Shi⁶, Lixia Jiang⁶, Xinqiong Yang⁶, John F Fullard¹¹, Jaroslav Bendl¹¹, Kiran Girdhar¹¹, Minsu Kim⁴, Xi Chen¹²; PsychENCODE Consortium; William J Greenleaf⁶, Laramie Duncan¹³, Hanlee P Ji⁸, Xiang Zhu¹⁴, Giltae Song¹⁵, Stephen B Montgomery¹⁶, Dean Palejev¹⁷, Heinrich Zu Dohna¹⁸, Panos Roussos¹⁹, Anshul Kundaje⁷, Joachim F Hallmayer¹³, Michael P Snyder⁶, Wing H Wong²⁰, Alexander E Urban²¹

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Maternal and Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
² Department of Statistics, Stanford University, Stanford, CA 94305, USA.
³ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Maternal and Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Statistics, Stanford University, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
⁴ School of Computer Science and Engineering, Pusan National University, Busan 46241, South Korea.
⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
⁶ Department of Genetics, Stanford University, Stanford, CA 94305, USA.
⁷ Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
⁸ Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
⁹ Department of Pathology, Stanford University, Stanford, CA 94305, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Maternal and Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Department of Statistics, Stanford University, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
¹³ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
¹⁴ Department of Statistics, Stanford University, Stanford, CA 94305, USA; Department of Statistics, Pennsylvania State University, University Park, PA 16802, USA; Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
¹⁵ School of Computer Science and Engineering, Pusan National University, Busan 46241, South Korea; Center for Artificial Intelligence Research, Pusan National University, Busan 46241, South Korea.
¹⁶ Department of Genetics, Stanford University, Stanford, CA 94305, USA; Maternal and Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
¹⁷ Institute of Mathematics and Informatics, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria.
¹⁸ Department of Biology, American University of Beirut, Beirut 11-0236, Lebanon.
¹⁹ Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY 10468, USA; Mental Illness Research Education and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY 10468, USA.
²⁰ Department of Statistics, Stanford University, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
²¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Maternal and Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].

PMID: 39353437
DOI: 10.1016/j.cell.2024.09.014

Abstract

Complex structural variations (cxSVs) are often overlooked in genome analyses due to detection challenges. We developed ARC-SV, a probabilistic and machine-learning-based method that enables accurate detection and reconstruction of cxSVs from standard datasets. By applying ARC-SV across 4,262 genomes representing all continental populations, we identified cxSVs as a significant source of natural human genetic variation. Rare cxSVs have a propensity to occur in neural genes and loci that underwent rapid human-specific evolution, including those regulating corticogenesis. By performing single-nucleus multiomics in postmortem brains, we discovered cxSVs associated with differential gene expression and chromatin accessibility across various brain regions and cell types. Additionally, cxSVs detected in brains of psychiatric cases are enriched for linkage with psychiatric GWAS risk alleles detected in the same brains. Furthermore, our analysis revealed significantly decreased brain-region- and cell-type-specific expression of cxSV genes, specifically for psychiatric cases, implicating cxSVs in the molecular etiology of major neuropsychiatric disorders.

Keywords: ARC-SV; GTEx; PsychENCODE; complex structural variation; cxSVs; human evolution; population genetics; psychiatric genetics; single-cell multiomics; structural variation.

MeSH terms

Brain* / metabolism
Chromatin / genetics
Chromatin / metabolism
Genetic Variation
Genome, Human*
Genome-Wide Association Study
Genomic Structural Variation
Humans
Machine Learning
Mental Disorders* / genetics
Tissue Donors

Substances

Chromatin

Abstract

MeSH terms

Substances

Grants and funding