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

Research output: Contribution to journalArticle

  • Yanni Zeng
  • Lynsey Hall
  • Blair H. Smith
  • Sandosh Padmanabhan
  • Cathryn M. Lewis
  • Naomi R Wray
  • Divya Mehta
  • Brenda 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

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


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.

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