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

Yanni Zeng, Pau Navarro, Masoud Shirali, David M. Howard, Mark J. Adams, Lynsey S. Hall, Toni Kim Clarke, 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 Milaneschi, Bernhard T. Baune & 20 others 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, Ian J. Deary, David J. Porteous, Chris S. Haley, Andrew M. McIntosh, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticleAcademicpeer-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 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.

Original languageEnglish
Pages (from-to)312-321
Number of pages10
JournalBiological Psychiatry
Volume82
Issue number5
DOIs
Publication statusPublished - 1 Sep 2017

Cite this

Zeng, Y., Navarro, P., Shirali, M., Howard, D. M., Adams, M. J., Hall, L. S., ... Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2017). Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder. Biological Psychiatry, 82(5), 312-321. https://doi.org/10.1016/j.biopsych.2016.12.012
Zeng, Yanni ; Navarro, Pau ; Shirali, Masoud ; Howard, David M. ; Adams, Mark J. ; Hall, Lynsey S. ; Clarke, Toni Kim ; Thomson, Pippa A. ; Smith, Blair H. ; Murray, Alison ; Padmanabhan, Sandosh ; Hayward, Caroline ; Boutin, Thibaud ; MacIntyre, Donald J. ; Lewis, Cathryn M. ; Wray, Naomi R. ; Mehta, Divya ; Penninx, Brenda W.J.H. ; Milaneschi, Yuri ; Baune, Bernhard T. ; Air, Tracy ; Hottenga, Jouke Jan ; Mbarek, Hamdi ; Castelao, Enrique ; Pistis, Giorgio ; Schulze, Thomas G. ; Streit, Fabian ; Forstner, Andreas J. ; Byrne, Enda M. ; Martin, Nicholas G. ; Breen, Gerome ; Müller-Myhsok, Bertram ; Lucae, Susanne ; Kloiber, Stefan ; Domenici, Enrico ; Deary, Ian J. ; Porteous, David J. ; Haley, Chris S. ; McIntosh, Andrew M. ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. / Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder. In: Biological Psychiatry. 2017 ; Vol. 82, No. 5. pp. 312-321.
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title = "Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder",
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 = "Genome-wide analyses, Haplotype block, HRHM, MDD, Regional heritability, TOX2",
author = "Yanni Zeng and Pau Navarro and Masoud Shirali and Howard, {David M.} and Adams, {Mark J.} and Hall, {Lynsey S.} and Clarke, {Toni Kim} and Thomson, {Pippa A.} and Smith, {Blair H.} and Alison Murray and Sandosh Padmanabhan and Caroline Hayward and Thibaud Boutin and MacIntyre, {Donald J.} and Lewis, {Cathryn M.} and Wray, {Naomi R.} and Divya Mehta and Penninx, {Brenda W.J.H.} and Yuri Milaneschi and Baune, {Bernhard T.} and Tracy Air and Hottenga, {Jouke Jan} and Hamdi Mbarek and Enrique Castelao and Giorgio Pistis and Schulze, {Thomas G.} and Fabian Streit and Forstner, {Andreas J.} and Byrne, {Enda M.} and Martin, {Nicholas G.} and Gerome Breen and Bertram M{\"u}ller-Myhsok and Susanne Lucae and Stefan Kloiber and Enrico Domenici and Deary, {Ian J.} and Porteous, {David J.} and Haley, {Chris S.} and McIntosh, {Andrew M.} and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium}",
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language = "English",
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pages = "312--321",
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Zeng, Y, Navarro, P, Shirali, M, Howard, DM, Adams, MJ, Hall, LS, Clarke, TK, Thomson, PA, Smith, BH, Murray, A, Padmanabhan, S, Hayward, C, Boutin, T, MacIntyre, DJ, Lewis, CM, Wray, NR, Mehta, D, Penninx, BWJH, Milaneschi, Y, Baune, BT, Air, T, Hottenga, JJ, Mbarek, H, Castelao, E, Pistis, G, Schulze, TG, Streit, F, Forstner, AJ, Byrne, EM, Martin, NG, Breen, G, Müller-Myhsok, B, Lucae, S, Kloiber, S, Domenici, E, Deary, IJ, Porteous, DJ, Haley, CS, McIntosh, AM & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium 2017, 'Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder' Biological Psychiatry, vol. 82, no. 5, pp. 312-321. https://doi.org/10.1016/j.biopsych.2016.12.012

Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder. / Zeng, Yanni; Navarro, Pau; Shirali, Masoud; Howard, David M.; Adams, Mark J.; Hall, Lynsey S.; Clarke, Toni Kim; Thomson, Pippa A.; Smith, Blair H.; Murray, Alison; Padmanabhan, Sandosh; Hayward, Caroline; Boutin, Thibaud; MacIntyre, Donald J.; Lewis, Cathryn M.; Wray, Naomi R.; Mehta, Divya; Penninx, Brenda W.J.H.; Milaneschi, Yuri; Baune, Bernhard T.; Air, Tracy; Hottenga, Jouke Jan; Mbarek, Hamdi; Castelao, Enrique; Pistis, Giorgio; Schulze, Thomas G.; Streit, Fabian; Forstner, Andreas J.; Byrne, Enda M.; Martin, Nicholas G.; Breen, Gerome; Müller-Myhsok, Bertram; Lucae, Susanne; Kloiber, Stefan; Domenici, Enrico; Deary, Ian J.; Porteous, David J.; Haley, Chris S.; McIntosh, Andrew M.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

In: Biological Psychiatry, Vol. 82, No. 5, 01.09.2017, p. 312-321.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder

AU - Zeng, Yanni

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, Bernhard 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 - Deary, Ian J.

AU - Porteous, David J.

AU - Haley, Chris S.

AU - McIntosh, Andrew M.

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

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 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.

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 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.

KW - Genome-wide analyses

KW - Haplotype block

KW - HRHM

KW - MDD

KW - Regional heritability

KW - TOX2

UR - http://www.scopus.com/inward/record.url?scp=85010952799&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2016.12.012

DO - 10.1016/j.biopsych.2016.12.012

M3 - Article

VL - 82

SP - 312

EP - 321

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 5

ER -