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; 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

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 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. 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 J. Deary, David J. Porteous, Chris S. Haley, Andrew M. McIntosh, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

^*Corresponding author for this work

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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 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 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

Bibliographical note

Acknowledgments and Disclosures:
This work was supported by the Wellcome Trust through a Strategic Award (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 (CZD/16/6).

We are grateful to the families who took part in GS:SFHS, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes academic researchers, clinic staff members, laboratory technicians, clerical workers, information technology staff members, statisticians, and research managers.

AMM has previously received grant support from Pfizer, Lilly, and Janssen. These studies are not connected to the current investigation. YZ acknowledges support from the China Scholarship Council. T-KC and AMM acknowledge with gratitude the financial support received for this work from the Dr Mortimer and Theresa Sackler Foundation. PAT, DJP, IJD, and AMM are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council (MRC) is gratefully acknowledged. DJM is an NHS Research Scotland (NRS) Fellow, funded by the Chief Scientist Office. PN and CSH acknowledge support from the MRC. All other authors report no biomedical financial interests or potential conflicts of interest.

GS:SFHS data are available to researchers on application to the Generation Scotland Access Committee (access: http://generationscotland.org). The managed access process ensures that approval is granted only to research that comes under the terms of participant consent.

Keywords

Genome-wide analyses
Haplotype block
HRHM
MDD
Regional heritability
TOX2

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Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder
© 2017 Society of Biological Psychiatry. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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Zeng, Y., 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., ... 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, 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

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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}",

note = "Acknowledgments and Disclosures: This work was supported by the Wellcome Trust through a Strategic Award (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 (CZD/16/6). We are grateful to the families who took part in GS:SFHS, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes academic researchers, clinic staff members, laboratory technicians, clerical workers, information technology staff members, statisticians, and research managers. AMM has previously received grant support from Pfizer, Lilly, and Janssen. These studies are not connected to the current investigation. YZ acknowledges support from the China Scholarship Council. T-KC and AMM acknowledge with gratitude the financial support received for this work from the Dr Mortimer and Theresa Sackler Foundation. PAT, DJP, IJD, and AMM are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council (MRC) is gratefully acknowledged. DJM is an NHS Research Scotland (NRS) Fellow, funded by the Chief Scientist Office. PN and CSH acknowledge support from the MRC. All other authors report no biomedical financial interests or potential conflicts of interest. GS:SFHS data are available to researchers on application to the Generation Scotland Access Committee (access: http://generationscotland.org). The managed access process ensures that approval is granted only to research that comes under the terms of participant consent.",

year = "2017",

month = sep,

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

language = "English",

volume = "82",

pages = "312--321",

journal = "Biological Psychiatry",

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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

N1 - Acknowledgments and Disclosures: This work was supported by the Wellcome Trust through a Strategic Award (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 (CZD/16/6). We are grateful to the families who took part in GS:SFHS, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes academic researchers, clinic staff members, laboratory technicians, clerical workers, information technology staff members, statisticians, and research managers. AMM has previously received grant support from Pfizer, Lilly, and Janssen. These studies are not connected to the current investigation. YZ acknowledges support from the China Scholarship Council. T-KC and AMM acknowledge with gratitude the financial support received for this work from the Dr Mortimer and Theresa Sackler Foundation. PAT, DJP, IJD, and AMM are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council (MRC) is gratefully acknowledged. DJM is an NHS Research Scotland (NRS) Fellow, funded by the Chief Scientist Office. PN and CSH acknowledge support from the MRC. All other authors report no biomedical financial interests or potential conflicts of interest. GS:SFHS data are available to researchers on application to the Generation Scotland Access Committee (access: http://generationscotland.org). The managed access process ensures that approval is granted only to research that comes under the terms of participant consent.

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.

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KW - Haplotype block

KW - HRHM

KW - MDD

KW - Regional heritability

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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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