TY - JOUR
T1 - Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries
AU - Talkowski, Michael E.
AU - Rosenfeld, Jill A.
AU - Blumenthal, Ian
AU - Pillalamarri, Vamsee
AU - Chiang, Colby
AU - Heilbut, Adrian
AU - Ernst, Carl
AU - Hanscom, Carrie
AU - Rossin, Elizabeth
AU - Lindgren, Amelia M.
AU - Pereira, Shahrin
AU - Ruderfer, Douglas
AU - Kirby, Andrew
AU - Ripke, Stephan
AU - Harris, David J.
AU - Lee, Ji Hyun
AU - Ha, Kyungsoo
AU - Kim, Hyung Goo
AU - Solomon, Benjamin D.
AU - Gropman, Andrea L.
AU - Lucente, Diane
AU - Sims, Katherine
AU - Ohsumi, Toshiro K.
AU - Borowsky, Mark L.
AU - Loranger, Stephanie
AU - Quade, Bradley
AU - Lage, Kasper
AU - Miles, Judith
AU - Wu, Bai Lin
AU - Shen, Yiping
AU - Neale, Benjamin
AU - Shaffer, Lisa G.
AU - Daly, Mark J.
AU - Morton, Cynthia C.
AU - Gusella, James F.
N1 - Funding Information:
We are grateful to all participating subjects and families and to the many healthcare professionals who have contributed to this study, including Mary-Alice Abbott, Darius J. Adams, Kwame Anyane-Yeboa, Stephen G. Bamforth, Tina Bartell, David P. Bick, Joann N. Bodurtha, Carol Clericuzio, Stephanie Cohen, Kristin Dalton, Maria Descartes, Joanne Milisa Drautz, Dawn L. Earl, Luis F. Escobar, Shannon Gerner, Edwin Guzman, Kenneth Handelman, Tim Heshka, Robert J. Hopkin, Micheil Innes, Debby Lambert, Emmanuelle Lemyre, Cynthia Lim, Livija Medne, Graciela Moya, Katie Rutledge, Wendy Smith, Mark Stephan, Darci Sternen, Katie Stoll, Paulien van Galen, Nancy J. Van Vranken, Erica Wahl, Susan E. Wiley, Amy L. White, Anne Woods, and Elaine H. Zackai. The invaluable control data for this study were provided by Pamela Sklar, Shaun Purcell, the International Schizophrenia Consortium, the Wellcome Trust Case Control Consortium, Evan Eichler, Bradley Coe, and Greg Cooper. We thank Tammy Gillis, Mary Anne Anderson, Jayla Ruliera, and Thon de Boer for technical assistance. We also thank Dennis Gurgul, Nilay Roy, and Brent Richter of Partners Research Computing at Massachusetts General Hospital, and contributing staff from Signature Genomic Laboratories and Children's Hospital Boston. This work was funded by grants GM061354 and HD065286 from the National Institutes of Health, the Simons Foundation Autism Research Initiative, and Autism Speaks. This research was also supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and Human Services. M.T. was supported by a National Institute of Mental Health National Research Service Award (MH087123) and an Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery Award. L.G.S. and J.A.R. are employees of Signature Genomic Laboratories, PerkinElmer.
PY - 2012/4/27
Y1 - 2012/4/27
N2 - Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g.; AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g.; CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g.; TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.
AB - Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g.; AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g.; CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g.; TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.
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U2 - 10.1016/j.cell.2012.03.028
DO - 10.1016/j.cell.2012.03.028
M3 - Article
C2 - 22521361
AN - SCOPUS:84860347597
SN - 0092-8674
VL - 149
SP - 525
EP - 537
JO - Cell
JF - Cell
IS - 3
ER -