@article{Zeng2016,
title = {Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder},
author = {Yanni Zeng ,Pau Navarr, Masoud Shirali, David M. Howard, Mark J. Adams, Lynsey S. Hall, Toni-Kim Clark, 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 Milaneschio, Bernhard T. Baunen, Tracy Airn, Jouke-Jan Hottengap, Hamdi Mbarekp, Enrique Castelaoq, Giorgio Pistisq, Thomas G. Schulzer, t, u, Fabian Streitv, Andreas J. Forstnerw, x, Enda M. Byrnel, Nicholas G. Martinm, Gerome Breenk, Bertram Müller-Myhsoks, Susanne Lucaes, Stefan Kloibers, Enrico DomeniciY,

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Ian J. Dearyd, e, f, David J. Porteousc, d, e, Chris S. Haleyb, g, Andrew M. McIntosha, },
url = {http://www.sciencedirect.com/science/article/pii/S0006322316331134},
year = {2016},
date = {2016-12-16},
journal = {Biological Psychiatry},
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 = {4844, Depressive disorder, genome-wide},
pubstate = {published},
tppubtype = {article}
}

@article{whalleyhc2016,
title = {Dissection of major depressive disorder using polygenic risk scores for schizophrenia in two independent cohorts},
author = {Whalley, H. C.
Adams, M. J.
Hall, L. S.
Clarke, T. K.
Fernandez-Pujals, A. M.
Gibson, J.
Wigmore, E.
Hafferty, J.
Hagenaars, S. P.
Davies, G.
Campbell, A.
Hayward, C.
Lawrie, S. M.
Porteous, D. J.
Deary, I. J.
McIntosh, A. M.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27801894},
year = {2016},
date = {2016-11-02},
journal = {Transl Psychiatry},
abstract = {Major depressive disorder (MDD) is known for its substantial clinical and suspected causal heterogeneity. It is characterized by low mood, psychomotor slowing and increased levels of the personality trait neuroticism; factors also associated with schizophrenia (SCZ). It is possible that some cases of MDD may have a substantial genetic loading for SCZ. The presence of SCZ-like MDD subgroups would be indicated by an interaction between MDD status and polygenic risk of SCZ on cognitive, personality and mood measures. Here, we hypothesized that higher SCZ polygenic risk would define larger MDD case-control differences in cognitive ability, and smaller differences in distress and neuroticism. Polygenic risk scores (PRSs) for SCZ and their association with cognitive variables, neuroticism, mood and psychological distress were estimated in a large population-based cohort (Generation Scotland: Scottish Family Health Study, GS:SFHS). The individuals were divided into those with, and without, depression (n=2587 and n=16 764, respectively) to test for the interactions between MDD status and schizophrenia risk. Replication was sought in UK Biobank (UKB; n=6049 and n=27 476 cases and controls, respectively). In both the cohorts, we found significant interactions between SCZ-PRS and MDD status for measures of psychological distress (betaGS=-0.04, PGS=0.014 and betaUKB=-0.09, PUKB0.001 for GS:SFHS and UKB, respectively) and neuroticism (betaGS=-0.04, PGS=0.002 and betaUKB=-0.06, PUKB=0.023). In both the cohorts, there was a reduction of case-control differences on a background of higher genetic risk of SCZ. These findings suggest that depression on a background of high genetic risk for SCZ may show attenuated associations with distress and neuroticism. This may represent a causally distinct form of MDD more closely related to SCZ.},
keywords = {Depressive disorder, genetics, schizophrenia},
pubstate = {published},
tppubtype = {article}
}