Cell Reports (Nov 2014)
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
Affiliations
- Panos Roussos
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Amanda C. Mitchell
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Georgios Voloudakis
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- John F. Fullard
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Venu M. Pothula
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Jonathan Tsang
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Eli A. Stahl
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Anastasios Georgakopoulos
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Douglas M. Ruderfer
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Alexander Charney
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Yukinori Okada
- Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 230-0045, Japan
- Katherine A. Siminovitch
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
- Jane Worthington
- Arthritis Research UK Centre for Genetics and Genomics, Musculoskeletal Research Centre, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9NT, UK
- Leonid Padyukov
- Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm 171 76, Sweden
- Lars Klareskog
- Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm 171 76, Sweden
- Peter K. Gregersen
- The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA
- Robert M. Plenge
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Soumya Raychaudhuri
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Menachem Fromer
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Shaun M. Purcell
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Kristen J. Brennand
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Nikolaos K. Robakis
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Eric E. Schadt
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Schahram Akbarian
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Pamela Sklar
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- DOI
- https://doi.org/10.1016/j.celrep.2014.10.015
- Journal volume & issue
-
Vol. 9,
no. 4
pp. 1417 – 1429
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.
