Do regional brain volumes and major depressive disorder share genetic architecture?: A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766)

E. M. Wigmore; T-K Clarke; D. M. Howard; M. J. Adams; L. S. Hall; Y. Zeng; J. Gibson; G. Davies; A. M. Fernandez-Pujals; P. A. Thomson; C. Hayward; B. H. Smith; L. J. Hocking; S. Padmanabhan; I. J. Deary; D. J. Porteous; K. K. Nicodemus; A. M. McIntosh

doi:10.1038/tp.2017.148

Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766)

E. M. Wigmore, T-K Clarke, D. M. Howard, M. J. Adams, L. S. Hall, Y. Zeng, J. Gibson, G. Davies, A. M. Fernandez-Pujals, P. A. Thomson, C. Hayward, B. H. Smith, L. J. Hocking, S. Padmanabhan, I. J. Deary, D. J. Porteous, K. K. Nicodemus, A. M. McIntosh

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Abstract

Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV.

Original language	English
Article number	e1205
Pages (from-to)	1-9
Number of pages	9
Journal	Translational Psychiatry
Volume	7
Issue number	8
DOIs	https://doi.org/10.1038/tp.2017.148
Publication status	Published - 15 Aug 2017

Bibliographical note

This investigation was supported by the Wellcome Trust 104036/Z/14/Z (STRADL, Stratifying Resilience and Depression Longitudinally). Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. We thank all families, practitioners and the Scottish School of Primary Care involved in the recruitment process as well as the entirety of Generation Scotland team; interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. We are grateful towards the Dr Mortimer and Theresa Sackler foundation for the financial support for this work. This research has been conducted using the UK Biobank resource and we would therefore like to thank all participants and coordinators in this cohort. The UK Biobank study was conducted under generic approval from the NHS National Research Ethics Service (approval letter dated 17 June 2011. Ref 11/NW/0362). Samples from the English Longitudinal Study of Ageing DNA Repository (EDNAR), which receives support from the National Institute on Aging (NIA) and the Economic and Social Research Council (ESRC), were used in this study. We thank contributors and the ELSA participants. IJD is supported by MRC and BBSRC funding to the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (MR/K026992/1).

Supplementary Information accompanies the paper on the Translational Psychiatry website (http://www.nature.com/tp)

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Journal Article

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Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766)
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Wigmore, E. M., Clarke, T.-K., Howard, D. M., Adams, M. J., Hall, L. S., Zeng, Y., Gibson, J., Davies, G., Fernandez-Pujals, A. M., Thomson, P. A., Hayward, C., Smith, B. H., Hocking, L. J., Padmanabhan, S., Deary, I. J., Porteous, D. J., Nicodemus, K. K., & McIntosh, A. M. (2017). Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766). Translational Psychiatry, 7(8), 1-9. Article e1205. https://doi.org/10.1038/tp.2017.148

Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766). / Wigmore, E. M.; Clarke, T-K; Howard, D. M. et al.
In: Translational Psychiatry, Vol. 7, No. 8, e1205, 15.08.2017, p. 1-9.

Research output: Contribution to journal › Article › peer-review

Wigmore, EM, Clarke, T-K, Howard, DM, Adams, MJ, Hall, LS, Zeng, Y, Gibson, J, Davies, G, Fernandez-Pujals, AM, Thomson, PA, Hayward, C, Smith, BH, Hocking, LJ, Padmanabhan, S, Deary, IJ, Porteous, DJ, Nicodemus, KK & McIntosh, AM 2017, 'Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766)', Translational Psychiatry, vol. 7, no. 8, e1205, pp. 1-9. https://doi.org/10.1038/tp.2017.148

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abstract = "Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV.",

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AU - Wigmore, E. M.

AU - Clarke, T-K

AU - Howard, D. M.

AU - Adams, M. J.

AU - Hall, L. S.

AU - Zeng, Y.

AU - Gibson, J.

AU - Davies, G.

AU - Fernandez-Pujals, A. M.

AU - Thomson, P. A.

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AU - Smith, B. H.

AU - Hocking, L. J.

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