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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84860347597&partnerID=8YFLogxK
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 -