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Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders

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Abstract

Migraine and major depressive disorder (MDD) are comorbid, moderately heritable and to some extent influenced by the same genes. In a previous paper, we suggested the possibility of causality (one trait causing the other) underlying this comorbidity. We present a new application of polygenic (genetic risk) score analysis to investigate the mechanisms underlying the genetic overlap of migraine and MDD. Genetic risk scores were constructed based on data from two discovery samples in which genome-wide association analyses (GWA) were performed for migraine and MDD, respectively. The Australian Twin Migraine GWA study (N = 6,350) included 2,825 migraine cases and 3,525 controls, 805 of whom met the diagnostic criteria for MDD. The RADIANT GWA study (N = 3,230) included 1,636 MDD cases and 1,594 controls. Genetic risk scores for migraine and for MDD were used to predict pure and comorbid forms of migraine and MDD in an independent Dutch target sample (NTR–NESDA, N = 2,966), which included 1,476 MDD cases and 1,058 migraine cases (723 of these individuals had both disorders concurrently). The observed patterns of prediction suggest that the ‘pure’ forms of migraine and MDD are genetically distinct disorders. The subgroup of individuals with comorbid MDD and migraine were genetically most similar to MDD patients. These results indicate that in at least a subset of migraine patients with MDD, migraine may be a symptom or consequence of MDD.

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Acknowledgments

The authors would like to thank Dr. Naomi Wray for her helpful comments and suggestions. This study was supported by: the EMGO+ Institute for Health and Care Research, the European Research Council (ERC-230374 and ERC-284167), the Netherlands Organization for Scientific Research (NWO 904-61-193, NWO/ZonMW 91210020). The infrastructure for the NESDA study (http://www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, Grant Number 10-000-1002) and is supported by participating universities and mental health care organisations [VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), Netherlands Institute for Health Services Research (NIVEL) and Netherlands Institute of Mental Health and Addiction (Trimbos Institute)]. Genotyping in the NTR and NESDA samples was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the US National Institute of Mental Health (NIMH) (MH081802). Statistical analyses were partly carried out on the Genetic Cluster Computer (NWO 480-05-003). Funding for the Australian cohort was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 443036, 496675, 496739, 552485, 552498, 613602, 613608, 613674 and 619667), the Australian Research Council (A7960034, A79906588, A79801419, DP0212016, DP0343921, FT0991022 and FT0991360), the EU FP5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (AA07535, AA10249, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951) and Center for Inherited Disease Research (Baltimore, MD, USA). We thank P.M. Visscher, D.L. Duffy, A.K. Henders, S.E. Medland, B. Usher, E. Souzeau, A. Kuot, A. McMellon, M.J. Wright, M.J. Campbell, A. Caracella, L. Bowdler, S. Smith, S.D. Gordon, B. Haddon, D. Smyth, H. Beeby, O. Zheng and B. Chapman for their input into project management, databases, phenotype collection, and sample collection, processing and genotyping. We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. Genotyping of the RADIANT study was funded by a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420). DeCC study collection was supported by the UK MRC (G0000647) and the GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428.

Conflict of interest

A.E. Farmer and P. McGuffin have received consultancy fees and honoraria for participating in expert panels for pharmaceutical companies including GlaxoSmithKline. The other authors report no conflicts of interest.

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Authors and Affiliations

  1. Department of Biological Psychology, VU University, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands

    Lannie Ligthart, Jouke-Jan Hottenga, Gonneke Willemsen, Jacqueline M. Vink, Christel M. Middeldorp & Dorret I. Boomsma

  2. EMGO+ Institute for Health and Care Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands

    Lannie Ligthart

  3. MRC SGDP Centre, Institute of Psychiatry, PO80, DeCrespigny Park, Denmark Hill, London, SE5 8AF, UK

    Cathryn M. Lewis, Anne E. Farmer, Ian W. Craig, Gerome Breen & Peter McGuffin

  4. Department of Child and Adolescent Psychiatry, GGZ inGeest/VU University Medical Center, A.J. Ernststraat 1187, 1081 HL, Amsterdam, The Netherlands

    Christel M. Middeldorp

  5. Queensland Brain Institute, The University of Queensland, QBI Building (#79), St Lucia, QLD, 4072, Australia

    Enda M. Byrne

  6. Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA

    Andrew C. Heath, Pamela A. F. Madden & Michele L. Pergadia

  7. QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Herston, QLD, 4029, Australia

    Grant W. Montgomery, Nicholas G. Martin & Dale R. Nyholt

  8. Department of Psychiatry, VU University Medical Center, A.J. Ernststraat 1187, 1081 HL, Amsterdam, The Netherlands

    Brenda W. J. H. Penninx

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  1. Lannie Ligthart
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  2. Jouke-Jan Hottenga
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  3. Cathryn M. Lewis
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  4. Anne E. Farmer
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  7. Gonneke Willemsen
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  8. Jacqueline M. Vink
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  12. Pamela A. F. Madden
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  13. Michele L. Pergadia
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  14. Grant W. Montgomery
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  17. Peter McGuffin
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  18. Dorret I. Boomsma
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  19. Dale R. Nyholt
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Corresponding author

Correspondence to Lannie Ligthart.

Additional information

D. I. Boomsma and D. R. Nyholt contributed equally to this work.

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Ligthart, L., Hottenga, JJ., Lewis, C.M. et al. Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders. Hum Genet 133, 173–186 (2014). https://doi.org/10.1007/s00439-013-1370-8

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  • DOI: https://doi.org/10.1007/s00439-013-1370-8

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