TY - JOUR
T1 - A Role for Noncoding Variation in Schizophrenia
AU - Roussos, Panos
AU - Mitchell, Amanda C.
AU - Voloudakis, Georgios
AU - Fullard, John F.
AU - Pothula, Venu M.
AU - Tsang, Jonathan
AU - Stahl, Eli A.
AU - Georgakopoulos, Anastasios
AU - Ruderfer, Douglas M.
AU - Charney, Alexander
AU - Okada, Yukinori
AU - Siminovitch, Katherine A.
AU - Worthington, Jane
AU - Padyukov, Leonid
AU - Klareskog, Lars
AU - Gregersen, Peter K.
AU - Plenge, Robert M.
AU - Raychaudhuri, Soumya
AU - Fromer, Menachem
AU - Purcell, Shaun M.
AU - Brennand, Kristen J.
AU - Robakis, Nikolaos K.
AU - Schadt, Eric E.
AU - Akbarian, Schahram
AU - Sklar, Pamela
N1 - Publisher Copyright:
© 2014 The Authors.
PY - 2014/11/20
Y1 - 2014/11/20
N2 - A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.
AB - A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.
UR - https://www.scopus.com/pages/publications/84912125156
U2 - 10.1016/j.celrep.2014.10.015
DO - 10.1016/j.celrep.2014.10.015
M3 - Article
C2 - 25453756
AN - SCOPUS:84912125156
SN - 2639-1856
VL - 9
SP - 1417
EP - 1429
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -