Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
28153336
TITLE
Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
Major depressive disorder (MDD) is the second largest cause of global disease burden. It has an estimated heritability of 37%, but published genome-wide association studies have so far identified few risk loci. Haplotype-block-based regional heritability mapping (HRHM) estimates the localized genetic variance explained by common variants within haplotype blocks, integrating the effects of multiple variants, and may be more powerful for identifying MDD-associated genomic regions.
METHODS NlmCategory: METHODS
We applied HRHM to Generation Scotland: The Scottish Family Health Study, a large family- and population-based Scottish cohort (N = 19,896). Single-single nucleotide polymorphism (SNP) and haplotype-based association tests were used to localize the association signal within the regions identified by HRHM. Functional prediction was used to investigate the effect of MDD-associated SNPs within the regions.
RESULTS NlmCategory: RESULTS
A haplotype block across a 24-kb region within the TOX2 gene reached genome-wide significance in HRHM. Single-SNP- and haplotype-based association tests demonstrated that five of nine genotyped SNPs and two haplotypes within this block were significantly associated with MDD. The expression of TOX2 and a brain-specific long noncoding RNA RP1-269M15.3 in frontal cortex and nucleus accumbens basal ganglia, respectively, were significantly regulated by MDD-associated SNPs within this region. Both the regional heritability and single-SNP associations within this block were replicated in the UK-Ireland group of the most recent release of the Psychiatric Genomics Consortium (PGC), the PGC2-MDD (Major Depression Dataset). The SNP association was also replicated in a depressive symptom sample that shares some individuals with the PGC2-MDD.
CONCLUSIONS NlmCategory: CONCLUSIONS
This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies.
Copyright 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2016 Dec 16
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2016/08/03
revised 2016/11/16
accepted 2016/12/13
entrez 2017/02/04 06:00
pubmed 2017/02/06 06:00
medline 2017/02/06 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Zeng Y Zeng Yanni Y Division of Psychiatry, University of Edinburgh, Edinburgh. Electronic address: y.zeng-6@sms.ed.ac.uk.
Navarro P Navarro Pau P Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh.
Shirali M Shirali Masoud M Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh; Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh.
Howard DM Howard David M DM Division of Psychiatry, University of Edinburgh, Edinburgh.
Adams MJ Adams Mark J MJ Division of Psychiatry, University of Edinburgh, Edinburgh.
Hall LS Hall Lynsey S LS Division of Psychiatry, University of Edinburgh, Edinburgh.
Clarke TK Clarke Toni-Kim TK Division of Psychiatry, University of Edinburgh, Edinburgh.
Thomson PA Thomson Pippa A PA Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh.
Smith BH Smith Blair H BH Department of Psychology, University of Edinburgh, Edinburgh; Division of Population Health Sciences, University of Dundee, Dundee.
Murray A Murray Alison A Division of Applied Health Sciences, University of Aberdeen, Aberdeen.
Padmanabhan S Padmanabhan Sandosh S Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow.
Hayward C Hayward Caroline C Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh.
Boutin T Boutin Thibaud T Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh.
MacIntyre DJ MacIntyre Donald J DJ Division of Psychiatry, University of Edinburgh, Edinburgh.
Lewis CM Lewis Cathryn M CM MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
Wray NR Wray Naomi R NR Queensland Brain Institute, University of Queensland, St. Lucia, Queensland.
Mehta D Mehta Divya D Queensland Brain Institute, University of Queensland, St. Lucia, Queensland.
Penninx BW Penninx Brenda W J H BW Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
Milaneschi Y Milaneschi Yuri Y Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
Baune BT Baune Bernhard T BT Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
Air T Air Tracy T Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
Hottenga JJ Hottenga Jouke-Jan JJ Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
Mbarek H Mbarek Hamdi H Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
Castelao E Castelao Enrique E Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
Pistis G Pistis Giorgio G Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
Schulze TG Schulze Thomas G TG Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University, Munich Cluster for Systems Neurology, Munich; Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Göttingen; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg.
Streit F Streit Fabian F Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim.
Forstner AJ Forstner Andreas J AJ Institute of Human Genetics, Life and Brain Center, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Byrne EM Byrne Enda M EM Queensland Brain Institute, University of Queensland, St. Lucia, Queensland.
Martin NG Martin Nicholas G NG School of Psychology, University of Queensland, St. Lucia, Queensland.
Breen G Breen Gerome G MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
Müller-Myhsok B Müller-Myhsok Bertram B Max Planck Institute of Psychiatry, Munich Cluster for Systems Neurology, Munich.
Lucae S Lucae Susanne S Max Planck Institute of Psychiatry, Munich Cluster for Systems Neurology, Munich.
Kloiber S Kloiber Stefan S Max Planck Institute of Psychiatry, Munich Cluster for Systems Neurology, Munich.
Domenici E Domenici Enrico E Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology, University of Trento, Trento, Italy.
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Deary IJ Deary Ian J IJ Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh; Department of Psychology, University of Edinburgh, Edinburgh.
Porteous DJ Porteous David J DJ Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh; Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh.
Haley CS Haley Chris S CS Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh; The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Edinburgh.
McIntosh AM McIntosh Andrew M AM Division of Psychiatry, University of Edinburgh, Edinburgh; Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh.
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: Biological psychiatry
ISOABBREVIATION: Biol. Psychiatry
YEAR: 2016
MONTH: Dec
DAY: 16
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1873-2402
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Biol Psychiatry
COUNTRY: United States
ISSNLINKING: 0006-3223
NLMUNIQUEID: 0213264
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
KEYWORD
Genome-wide analyses
HRHM
Haplotype block
MDD
Regional heritability
TOX2
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's