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

Zeng Yanni; 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; Bernard 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; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Ian J. Deary; David J. Porteous; Chris S. Haley; Andrew M. 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

Zeng Yanni (Lead / Corresponding author), 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, Bernard 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, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Ian J. Deary, David J. Porteous, Chris S. Haley, Andrew M. McIntosh

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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
Number of pages	10
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 Sept 2017

Keywords

Regional heritability
HRHM
TOX2
MDD
Haplotype block
Genome-wide analysis

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

keywords = "Regional heritability, HRHM, TOX2, MDD, Haplotype block, Genome-wide analysis",

author = "Zeng Yanni and Pau Navarro and Masoud Shirali and Howard, {David M.} and Adams, {Mark J.} and Hall, {Lynsey S.} and Toni-Kim Clarke 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, {Bernard 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 {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Deary, {Ian J.} and Porteous, {David J.} and Haley, {Chris S.} and McIntosh, {Andrew M.}",

note = "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.",

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

language = "English",

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journal = "Biological Psychiatry",

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Yanni, Z, Navarro, P, Shirali, M, Howard, DM, Adams, MJ, Hall, LS, Clarke, T-K, 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, 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, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Deary, IJ, Porteous, DJ, Haley, CS & McIntosh, AM 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 - 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

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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 -

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

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

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