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.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; James J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center (MIRECC), 130 West Kingsbridge Road, Bronx, NY 10468, USA. Electronic address: panagiotis.roussos@mssm.edu.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Mitchell
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Georgios
authors.initials: G
authors.lastname: Voloudakis
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Fullard
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Venu M
authors.initials: VM
authors.lastname: Pothula
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tsang
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgakopoulos
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ruderfer
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Charney
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 230-0045, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Toronto General Research Institute, Toronto, ON M5G 2M9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 2J7, Canada.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
authors.affiliation: 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; National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Menachem
authors.initials: M
authors.lastname: Fromer
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Brennand
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: pamela.sklar@mssm.edu.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000235:genetics; D021901:DNA, Intergenic / Q000235:genetics*; D030541:Databases, Genetic; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D058977:Molecular Sequence Annotation; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D021901:DNA, Intergenic