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



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.



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.



This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies.
Division of Psychiatry, University of Edinburgh, Edinburgh. Electronic address: y.zeng-6@sms.ed.ac.uk.
Yanni
Y
Zeng
Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh.
Pau
P
Navarro
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.
Masoud
M
Shirali
Division of Psychiatry, University of Edinburgh, Edinburgh.
David M
DM
Howard
Division of Psychiatry, University of Edinburgh, Edinburgh.
Mark J
MJ
Adams
Division of Psychiatry, University of Edinburgh, Edinburgh.
Lynsey S
LS
Hall
Division of Psychiatry, University of Edinburgh, Edinburgh.
Toni-Kim
TK
Clarke
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh.
Pippa A
PA
Thomson
Department of Psychology, University of Edinburgh, Edinburgh; Division of Population Health Sciences, University of Dundee, Dundee.
Blair H
BH
Smith
Division of Applied Health Sciences, University of Aberdeen, Aberdeen.
Alison
A
Murray
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow.
Sandosh
S
Padmanabhan
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh.
Caroline
C
Hayward
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh.
Thibaud
T
Boutin
Division of Psychiatry, University of Edinburgh, Edinburgh.
Donald J
DJ
MacIntyre
MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
Cathryn M
CM
Lewis
Queensland Brain Institute, University of Queensland, St. Lucia, Queensland.
Naomi R
NR
Wray
Queensland Brain Institute, University of Queensland, St. Lucia, Queensland.
Divya
D
Mehta
Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
Brenda W J H
BWJH
Penninx
Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
Yuri
Y
Milaneschi
Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
Bernhard T
BT
Baune
Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
Tracy
T
Air
Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
Jouke-Jan
JJ
Hottenga
Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
Hamdi
H
Mbarek
Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
Enrique
E
Castelao
Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
Giorgio
G
Pistis
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.
Thomas G
TG
Schulze
Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim.
Fabian
F
Streit
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.
Andreas J
AJ
Forstner
Queensland Brain Institute, University of Queensland, St. Lucia, Queensland.
Enda M
EM
Byrne
School of Psychology, University of Queensland, St. Lucia, Queensland.
Nicholas G
NG
Martin
MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
Gerome
G
Breen
Max Planck Institute of Psychiatry, Munich Cluster for Systems Neurology, Munich.
Bertram
B
Müller-Myhsok
Max Planck Institute of Psychiatry, Munich Cluster for Systems Neurology, Munich.
Susanne
S
Lucae
Max Planck Institute of Psychiatry, Munich Cluster for Systems Neurology, Munich.
Stefan
S
Kloiber
Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology, University of Trento, Trento, Italy.
Enrico
E
Domenici
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.
Ian J
IJ
Deary
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.
David J
DJ
Porteous
Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh; The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Edinburgh.
Chris S
CS
Haley
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.
Andrew M
AM
McIntosh
D015331:Cohort Studies; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D024002:HMGB Proteins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007494:Ireland; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom
D024002:HMGB Proteins; C574439:Tox2 protein, human
Genome-wide analyses; HRHM; Haplotype block; MDD; Regional heritability; TOX2