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

Yanni Zeng, Pau Navarro, Masoud Shirali, David Howard, Mark Adams, Lynsey Hall, Toni-Kim Clarke, Philippa Thomson, Blair H. Smith, Alison Murray, Sandosh Padmanabhan, Caroline Hayward, Thibaud Boutin, Donald MacIntyre, Cathryn M. Lewis, Naomi R Wray, Divya Mehta, Brenda Penninx, Yuri Milaneschi, Bernhard T. BauneTracy 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, Ian Deary, David Porteous, Christopher Haley, Andrew McIntosh

Research output: Contribution to journalArticlepeer-review

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 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.
Original languageEnglish
Pages (from-to)312-321
JournalBiological Psychiatry
Volume82
Issue number5
Early online date16 Dec 2016
DOIs
Publication statusPublished - 1 Sep 2017

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