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. 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; Ian Deary; David Porteous; Christopher Haley; Andrew McIntosh

doi:10.1016/j.biopsych.2016.12.012

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 journal › Article › peer-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 language	English
Pages (from-to)	312-321
Journal	Biological Psychiatry
Volume	82
Issue number	5
Early online date	16 Dec 2016
DOIs	https://doi.org/10.1016/j.biopsych.2016.12.012
Publication status	Published - 1 Sep 2017

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10.1016/j.biopsych.2016.12.012

Genome-wide regional heritability mapping identifies a locus within the TOX2 gene associated with Major Depressive DisorderAccepted author manuscript, 1.27 MB

http://www.biologicalpsychiatryjournal.com/article/S0006-3223%2816%2933113-4/fulltext?rss=yes

Stratifying Resilience and Depression Longitudinally
McIntosh, A., Deary, I., Evans, K., Haley, C. & Porteous, D.
UK-based charities
1/01/15 → 30/06/21
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research
Generation Scotland
Porteous, D.
UK central government bodies/local authorities, health and hospital authorities
1/04/11 → 31/03/14
Project: Research

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Zeng, Y., Navarro, P., Shirali, M., Howard, D., Adams, M., Hall, L., Clarke, T-K., Thomson, P., Smith, B. H., Murray, A., Padmanabhan, S., Hayward, C., Boutin, T., MacIntyre, D., Lewis, C. M., Wray, N. R., Mehta, D., Penninx, B., Milaneschi, Y., ... McIntosh, A. (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

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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 maybe more powerful for identifying MDD-associated genomic region.Methods: We applied HRHM to GS:SFHS, a large family and population basedScottish 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.",

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

year = "2017",

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doi = "10.1016/j.biopsych.2016.12.012",

language = "English",

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pages = "312--321",

journal = "Biological Psychiatry",

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publisher = "Elsevier",

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Zeng, Y, Navarro, P, Shirali, M, Howard, D, Adams, M, Hall, L, Clarke, T-K, Thomson, P, Smith, BH, Murray, A, Padmanabhan, S, Hayward, C , Boutin, T , MacIntyre, D, Lewis, CM, Wray, NR, Mehta, D, Penninx, B, Milaneschi, Y, Baune, BT, Air, T, Hottenga, J-J, 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, I, Porteous, D, Haley, C & McIntosh, A 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

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

AU - Adams, Mark

AU - Hall, Lynsey

AU - Clarke, Toni-Kim

AU - Thomson, Philippa

AU - Smith, Blair H.

AU - Murray, Alison

AU - Padmanabhan, Sandosh

AU - Hayward, Caroline

AU - Boutin, Thibaud

AU - MacIntyre, Donald

AU - Lewis, Cathryn M.

AU - Wray, Naomi R

AU - Mehta, Divya

AU - Penninx, Brenda

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

AU - Porteous, David

AU - Haley, Christopher

AU - McIntosh, Andrew

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 basedScottish 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 basedScottish 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.

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 -

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

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Projects

Stratifying Resilience and Depression Longitudinally

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Generation Scotland

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