Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder

Yanni Zeng; Pau Navarro; Masoud Shirali; David M Howard; Mark J Adams; Lynsey S Hall; Toni-Kim Clarke; Pippa A Thomson; Blair H Smith; Alison Murray; Sandosh Padmanabhan; Caroline Hayward; Thibaud Boutin; Donald J MacIntyre; Cathryn M Lewis; Naomi R Wray; Divya Mehta; Brenda W J H Penninx; Yuri Milaneschi; Bernhard T Baune; Tracy Air; Jouke-Jan Hottenga; Hamdi Mbarek; Enrique Castelao; Giorgio Pistis; Thomas G Schulze; Fabian Streit; Andreas J Forstner; Enda M Byrne; Nicholas G Martin; Gerome Breen; Bertram Müller-Myhsok; Susanne Lucae; Stefan Kloiber; Enrico Domenici; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Ian J Deary; David J Porteous; Chris S Haley; Andrew M McIntosh

doi:10.1016/j.biopsych.2016.12.012

Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder

Biol Psychiatry. 2017 Sep 1;82(5):312-321. doi: 10.1016/j.biopsych.2016.12.012. Epub 2016 Dec 16.

Authors

Yanni Zeng¹, Pau Navarro², Masoud Shirali³, David M Howard⁴, Mark J Adams⁴, Lynsey S Hall⁴, Toni-Kim Clarke⁴, Pippa A Thomson⁵, Blair H Smith⁶, Alison Murray⁷, Sandosh Padmanabhan⁸, Caroline Hayward⁹, Thibaud Boutin⁹, Donald J MacIntyre⁴, Cathryn M Lewis¹⁰, Naomi R Wray¹¹, Divya Mehta¹¹, Brenda W J H Penninx¹², Yuri Milaneschi¹², Bernhard T Baune¹³, Tracy Air¹³, Jouke-Jan Hottenga¹⁴, Hamdi Mbarek¹⁴, Enrique Castelao¹⁵, Giorgio Pistis¹⁵, Thomas G Schulze¹⁶, Fabian Streit¹⁷, Andreas J Forstner¹⁸, Enda M Byrne¹¹, Nicholas G Martin¹⁹, Gerome Breen¹⁰, Bertram Müller-Myhsok²⁰, Susanne Lucae²⁰, Stefan Kloiber²⁰, Enrico Domenici²¹; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Ian J Deary²², David J Porteous²³, Chris S Haley²⁴, Andrew M McIntosh²⁵

Affiliations

¹ Division of Psychiatry, University of Edinburgh, Edinburgh. Electronic address: y.zeng-6@sms.ed.ac.uk.
² Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh.
³ 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.
⁴ Division of Psychiatry, University of Edinburgh, Edinburgh.
⁵ Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh.
⁶ Department of Psychology, University of Edinburgh, Edinburgh; Division of Population Health Sciences, University of Dundee, Dundee.
⁷ Division of Applied Health Sciences, University of Aberdeen, Aberdeen.
⁸ Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow.
⁹ Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh.
¹⁰ MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
¹¹ Queensland Brain Institute, University of Queensland, St. Lucia, Queensland.
¹² Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
¹³ Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
¹⁴ Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
¹⁵ Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
¹⁶ 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.
¹⁷ Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim.
¹⁸ 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.
¹⁹ School of Psychology, University of Queensland, St. Lucia, Queensland.
²⁰ Max Planck Institute of Psychiatry, Munich Cluster for Systems Neurology, Munich.
²¹ Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology, University of Trento, Trento, Italy.
²² 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.
²³ 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.
²⁴ Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh; The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Edinburgh.
²⁵ 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.

Abstract

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: 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: 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: This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies.

Keywords: Genome-wide analyses; HRHM; Haplotype block; MDD; Regional heritability; TOX2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Depressive Disorder, Major / genetics*
Female
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study
HMGB Proteins / genetics*
Haplotypes*
Humans
Ireland
Male
Middle Aged
Polymorphism, Single Nucleotide*
United Kingdom

Substances

HMGB Proteins
Tox2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding