Genome-wide regional heritability mapping identifies a locus within the TOX2 gene associated with Major Depressive Disorder

TY - JOUR

T1 - Genome-wide regional heritability mapping identifies a locus within the TOX2 gene associated with Major Depressive Disorder

AU - Yanni, Zeng

AU - Navarro, Pau

AU - Shirali, Masoud

AU - Howard, David M.

AU - Adams, Mark J.

AU - Hall, Lynsey S.

AU - Clarke, Toni-Kim

AU - Thomson, Pippa A.

AU - Smith, Blair H.

AU - Murray, Alison

AU - Padmanabhan, Sandosh

AU - Hayward, Caroline

AU - Boutin, Thibaud

AU - MacIntyre, Donald J.

AU - Lewis, Cathryn M.

AU - Wray, Naomi R.

AU - Mehta, Divya

AU - Penninx, Brenda W. J. H.

AU - Milaneschi, Yuri

AU - Baune, Bernard T.

AU - Air, Tracy

AU - Hottenga, Jouke-Jan

AU - Mbarek, Hamdi

AU - Castelao, Enrique

AU - Pistis, Giorgio

AU - Schulze, Thomas G.

AU - Streit, Fabian

AU - Forstner, Andreas J.

AU - Byrne, Enda M.

AU - Martin, Nicholas G.

AU - Breen, Gerome

AU - Müller-Myhsok, Bertram

AU - Lucae, Susanne

AU - Kloiber, Stefan

AU - Domenici, Enrico

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Deary, Ian J.

AU - Porteous, David J.

AU - Haley, Chris S.

AU - McIntosh, Andrew M.

N1 - This work is supported by the Wellcome Trust through a Strategic Award, reference 104036/Z/14/Z. The Chief Scientist Office of the Scottish Government and the Scottish Funding Council provided core support for Generation Scotland. GS:SFHS was funded by a grant from the Scottish Government Health Department, Chief Scientist Office, number 410 CZD/16/6.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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 maybe more powerful for identifying MDD-associated genomic region. Methods: We applied HRHM to GS:SFHS, a large family and population based Scottish cohort (N=19,896). Single-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 24kb region within the TOX2 gene reached genome-wide significance in HRHM. Single-SNP and haplotype-based association tests demonstrated that five out of nine genotyped SNPs and two haplotypes within this block were significantly associated with MDD. The expression of TOX2 and a brain-specific LncRNA 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 (PGC2-MDD). The SNP-association was also replicated in a depressive symptom sample that shares some individuals with PGC2-MDD. Conclusion: This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies.

AB - 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 maybe more powerful for identifying MDD-associated genomic region. Methods: We applied HRHM to GS:SFHS, a large family and population based Scottish cohort (N=19,896). Single-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 24kb region within the TOX2 gene reached genome-wide significance in HRHM. Single-SNP and haplotype-based association tests demonstrated that five out of nine genotyped SNPs and two haplotypes within this block were significantly associated with MDD. The expression of TOX2 and a brain-specific LncRNA 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 (PGC2-MDD). The SNP-association was also replicated in a depressive symptom sample that shares some individuals with PGC2-MDD. Conclusion: This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies.

KW - Regional heritability

KW - HRHM

KW - TOX2

KW - MDD

KW - Haplotype block

KW - Genome-wide analysis

UR - https://www.scopus.com/pages/publications/85010952799

U2 - 10.1016/j.biopsych.2016.12.012

DO - 10.1016/j.biopsych.2016.12.012

M3 - Article

C2 - 28153336

AN - SCOPUS:85010952799

SN - 0006-3223

VL - 82

SP - 312

EP - 321

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 5

ER -