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Human Genetics

, Volume 133, Issue 2, pp 173–186 | Cite as

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

  • Lannie Ligthart
  • Jouke-Jan Hottenga
  • Cathryn M. Lewis
  • Anne E. Farmer
  • Ian W. Craig
  • Gerome Breen
  • Gonneke Willemsen
  • Jacqueline M. Vink
  • Christel M. Middeldorp
  • Enda M. Byrne
  • Andrew C. Heath
  • Pamela A. F. Madden
  • Michele L. Pergadia
  • Grant W. Montgomery
  • Nicholas G. Martin
  • Brenda W. J. H. Penninx
  • Peter McGuffin
  • Dorret I. Boomsma
  • Dale R. Nyholt
Original Investigation

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.

Keywords

Migraine Major Depressive Disorder Latent Class Analysis Genetic Risk Score Major Depressive Disorder Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Ethical standard

All experiments comply with the current laws of the country in which they were performed.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Lannie Ligthart
    • 1
    • 2
  • Jouke-Jan Hottenga
    • 1
  • Cathryn M. Lewis
    • 3
  • Anne E. Farmer
    • 3
  • Ian W. Craig
    • 3
  • Gerome Breen
    • 3
  • Gonneke Willemsen
    • 1
  • Jacqueline M. Vink
    • 1
  • Christel M. Middeldorp
    • 1
    • 4
  • Enda M. Byrne
    • 5
  • Andrew C. Heath
    • 6
  • Pamela A. F. Madden
    • 6
  • Michele L. Pergadia
    • 6
  • Grant W. Montgomery
    • 7
  • Nicholas G. Martin
    • 7
  • Brenda W. J. H. Penninx
    • 8
  • Peter McGuffin
    • 3
  • Dorret I. Boomsma
    • 1
  • Dale R. Nyholt
    • 7
  1. 1.Department of Biological PsychologyVU UniversityAmsterdamThe Netherlands
  2. 2.EMGO+ Institute for Health and Care ResearchVU University Medical CenterAmsterdamThe Netherlands
  3. 3.MRC SGDP CentreInstitute of PsychiatryLondonUK
  4. 4.Department of Child and Adolescent PsychiatryGGZ inGeest/VU University Medical CenterAmsterdamThe Netherlands
  5. 5.Queensland Brain InstituteThe University of QueenslandSt LuciaAustralia
  6. 6.Department of PsychiatryWashington University School of MedicineSt. LouisUSA
  7. 7.QIMR Berghofer Medical Research InstituteRoyal Brisbane HospitalHerstonAustralia
  8. 8.Department of PsychiatryVU University Medical CenterAmsterdamThe Netherlands

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