A role for noncoding variation in schizophrenia.

Panos Roussos; Amanda C Mitchell; Georgios Voloudakis; John F Fullard; Venu M Pothula; Jonathan Tsang; Eli A Stahl; Anastasios Georgakopoulos; Douglas M Ruderfer; Alexander Charney; Yukinori Okada; Katherine A Siminovitch; Jane Worthington; Leonid Padyukov; Lars Klareskog; Peter K Gregersen; Robert M Plenge; Soumya Raychaudhuri; Menachem Fromer; Shaun M Purcell; Kristen J Brennand; Nikolaos K Robakis; Eric E Schadt; Schahram Akbarian; Pamela Sklar

doi:10.1016/j.celrep.2014.10.015

A role for noncoding variation in schizophrenia.

Panos Roussos, Amanda C Mitchell, Georgios Voloudakis, John F Fullard, Venu M Pothula, Jonathan Tsang, Eli A Stahl, Anastasios Georgakopoulos, Douglas M Ruderfer, Alexander Charney, Yukinori Okada, Katherine A Siminovitch, Jane Worthington, Leonid Padyukov, Lars Klareskog, Peter K Gregersen, Robert M Plenge, Soumya Raychaudhuri, Menachem Fromer, Shaun M PurcellKristen J Brennand, Nikolaos K Robakis, Eric E Schadt, Schahram Akbarian, Pamela Sklar

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1417-1429
Journal	Cell Reports
Volume	9
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2014.10.015
Publication status	Published - 20 Nov 2014

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10.1016/j.celrep.2014.10.015

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Roussos, P., Mitchell, A. C., Voloudakis, G., Fullard, J. F., Pothula, V. M., Tsang, J., Stahl, E. A., Georgakopoulos, A., Ruderfer, D. M., Charney, A., Okada, Y., Siminovitch, K. A., Worthington, J., Padyukov, L., Klareskog, L., Gregersen, P. K., Plenge, R. M., Raychaudhuri, S., Fromer, M., ... Sklar, P. (2014). A role for noncoding variation in schizophrenia. Cell Reports, 9(4), 1417-1429. https://doi.org/10.1016/j.celrep.2014.10.015

@article{5619eb6952ee4a14b0b5319a4df17700,

title = "A role for noncoding variation in schizophrenia.",

abstract = "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.",

author = "Panos Roussos and Mitchell, {Amanda C} and Georgios Voloudakis and Fullard, {John F} and Pothula, {Venu M} and Jonathan Tsang and Stahl, {Eli A} and Anastasios Georgakopoulos and Ruderfer, {Douglas M} and Alexander Charney and Yukinori Okada and Siminovitch, {Katherine A} and Jane Worthington and Leonid Padyukov and Lars Klareskog and Gregersen, {Peter K} and Plenge, {Robert M} and Soumya Raychaudhuri and Menachem Fromer and Purcell, {Shaun M} and Brennand, {Kristen J} and Robakis, {Nikolaos K} and Schadt, {Eric E} and Schahram Akbarian and Pamela Sklar",

note = ", Wellcome Trust, United Kingdom",

year = "2014",

month = nov,

day = "20",

doi = "10.1016/j.celrep.2014.10.015",

language = "English",

volume = "9",

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journal = "Cell Reports",

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Roussos, P, Mitchell, AC, Voloudakis, G, Fullard, JF, Pothula, VM, Tsang, J, Stahl, EA, Georgakopoulos, A, Ruderfer, DM, Charney, A, Okada, Y, Siminovitch, KA, Worthington, J, Padyukov, L, Klareskog, L, Gregersen, PK, Plenge, RM, Raychaudhuri, S, Fromer, M, Purcell, SM, Brennand, KJ, Robakis, NK, Schadt, EE, Akbarian, S & Sklar, P 2014, 'A role for noncoding variation in schizophrenia.', Cell Reports, vol. 9, no. 4, pp. 1417-1429. https://doi.org/10.1016/j.celrep.2014.10.015

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 - , Wellcome Trust, United Kingdom

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.

U2 - 10.1016/j.celrep.2014.10.015

DO - 10.1016/j.celrep.2014.10.015

M3 - Article

C2 - 25453756

VL - 9

SP - 1417

EP - 1429

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

A role for noncoding variation in schizophrenia.

Abstract

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