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Human Genetics

, Volume 134, Issue 10, pp 1079–1087 | Cite as

Common polygenic variation contributes to risk of migraine in the Norfolk Island population

  • A. J. Rodriguez-Acevedo
  • M. A. Ferreira
  • Miles C. Benton
  • Melanie A. Carless
  • Harald H. Goring
  • Joanne E. Curran
  • John Blangero
  • R. A. Lea
  • L. R. GriffithsEmail author
Original Investigation

Abstract

Migraine has been defined as a common disabling primary headache disorder. Epidemiology studies have provided with the undeniable evidence of genetic components as active players in the development of the disease under a polygenic model in which multiple risk alleles exert modest individual effects. Our objective was to test the contribution of a polygenic effect to migraine risk in the Norfolk Island population using a panel of SNPs reported to be disease associated in published migraine GWAS. We also investigated whether individual SNPs were associated with gene expression levels measured in whole blood. Polygenic scores were calculated in a total of 285 related individuals (74 cases, 211 controls) from the Norfolk Island using 51 SNPs previously reported to be associated with migraine in published GWAS. The association between polygenic score and migraine case–control status was tested using logistic regression. Results indicate that a migraine polygenic risk score was associated with migraine case–control status in this population (P = 0.016). This supports the hypothesis that multiple SNPs with weak effects collectively contribute to migraine risk in this population. Amongst the SNPs included in the polygenic model, four were associated with the expression of the USMG5 gene, including rs171251 (P = 0.012). Results from this study provide evidence for a polygenic contribution to migraine risk in an isolated population and highlight specific SNPs that regulate the expression of USMG5, a gene critical for mitochondrial function.

Keywords

Migraine Migraine With Aura Familial Hemiplegic Migraine Maple Syrup Urine Disease Polygenic Model 
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

This research was supported by funding from a National Health and Medical Research Council of Australia project grant. A.J.R.A was supported by a QUT Postgraduate Research Award (QUTPRA) and the Australian Postgraduate Award (APA) Scholarships. M.C.B. was supported by a Corbett Postgraduate Research Scholarship, and R.A.L. was partially supported by a Corbett Research and a Griffith University Areas of Strategic Investment for Chronic Disease Fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

439_2015_1587_MOESM1_ESM.docx (26 kb)
Supplementary material 1 (DOCX 26 kb)

References

  1. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30(1):97–101CrossRefPubMedGoogle Scholar
  2. Alvarez V, Corao AI, Alonso-Montes C, Sanchez-Ferrero E, De Mena L, Morales B, Garcia-Castro M, Coto E (2008) Mitochondrial transcription factor A (TFAM) gene variation and risk of late-onset Alzheimer’s disease. J Alzheimers Dis 13(3):275–280PubMedGoogle Scholar
  3. Aly M, Wiklund F, Xu J, Isaacs WB, Eklund M, D’Amato M, Adolfsson J, Gronberg H (2011) Polygenic risk score improves prostate cancer risk prediction: results from the Stockholm-1 cohort study. Eur Urol 60(1):21–28PubMedCentralCrossRefPubMedGoogle Scholar
  4. Ambrosini A, D’Onofrio M, Grieco GS, Di Mambro A, Montagna G, Fortini D, Nicoletti F, Nappi G, Sances G, Schoenen J, Buzzi MG, Santorelli FM, Pierelli F (2005) Familial basilar migraine associated with a new mutation in the ATP1A2 gene. Neurology 65(11):1826–1828CrossRefPubMedGoogle Scholar
  5. Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, Kallela M, Malik R, de Vries B, Terwindt G, Medland SE, Todt U, McArdle WL, Quaye L, Koiranen M, Ikram MA, Lehtimaki T, Stam AH, Ligthart L, Wedenoja J, Dunham I, Neale BM, Palta P, Hamalainen E, Schurks M, Rose LM, Buring JE, Ridker PM, Steinberg S, Stefansson H, Jakobsson F, Lawlor DA, Evans DM, Ring SM, Farkkila M, Artto V, Kaunisto MA, Freilinger T, Schoenen J, Frants RR, Pelzer N, Weller CM, Zielman R, Heath AC, Madden PA, Montgomery GW, Martin NG, Borck G, Gobel H, Heinze A, Heinze-Kuhn K, Williams FM, Hartikainen AL, Pouta A, van den Ende J, Uitterlinden AG, Hofman A, Amin N, Hottenga JJ, Vink JM, Heikkila K, Alexander M, Muller-Myhsok B, Schreiber S, Meitinger T, Wichmann HE, Aromaa A, Eriksson JG, Traynor BJ, Trabzuni D, Rossin E, Lage K, Jacobs SB, Gibbs JR, Birney E, Kaprio J, Penninx BW, Boomsma DI, van Duijn C, Raitakari O, Jarvelin MR, Zwart JA, Cherkas L, Strachan DP, Kubisch C, Ferrari MD, van den Maagdenberg AM, Dichgans M, Wessman M, Smith GD, Stefansson K, Daly MJ, Nyholt DR, Chasman DI, Palotie A, C. North American Brain Expression, U. K. B. E. Consortium and C. International Headache Genetics (2013) Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet 45(8):912–917PubMedCentralCrossRefPubMedGoogle Scholar
  6. Beck T, Hastings RK, Gollapudi S, Free RC, Brookes AJ (2014) GWAS Central: a comprehensive resource for the comparison and interrogation of genome-wide association studies. Eur J Hum Genet 22(7):949–952PubMedCentralCrossRefPubMedGoogle Scholar
  7. Bellis C, Cox HC, Ovcaric M, Begley KN, Lea RA, Quinlan S, Burgner D, Heath SC, Blangero J, Griffiths LR (2008) Linkage disequilibrium analysis in the genetically isolated Norfolk Island population. Heredity (Edinb) 100(4):366–373CrossRefGoogle Scholar
  8. Benton MC, Lea RA, Macartney-Coxson D, Carless MA, Goring HH, Bellis C, Hanna M, Eccles D, Chambers GK, Curran JE, Harper JL, Blangero J, Griffiths LR (2013) Mapping eQTLs in the Norfolk Island genetic isolate identifies candidate genes for CVD risk traits. Am J Hum Genet 93(6):1087–1099PubMedCentralCrossRefPubMedGoogle Scholar
  9. Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, Krainc D (2005) Genome-wide expression profiling of human blood reveals biomarkers for Huntington’s disease. Proc Natl Acad Sci U S A 102(31):11023–11028PubMedCentralCrossRefPubMedGoogle Scholar
  10. Chasman DI, Schurks M, Anttila V, de Vries B, Schminke U, Launer LJ, Terwindt GM, van den Maagdenberg AM, Fendrich K, Volzke H, Ernst F, Griffiths LR, Buring JE, Kallela M, Freilinger T, Kubisch C, Ridker PM, Palotie A, Ferrari MD, Hoffmann W, Zee RY, Kurth T (2011) Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 43(7):695–698PubMedCentralCrossRefPubMedGoogle Scholar
  11. Chuang DT, Shih VE (2001) Maple syrup urine disease (branched-chain ketoaciduria). Metabolic and molecular bases of inherited disease. M. Hill, New York, pp 1971–2005Google Scholar
  12. Cox HC, Lea RA, Bellis C, Carless M, Dyer TD, Curran J, Charlesworth J, Macgregor S, Nyholt D, Chasman D, Ridker PM, Schurks M, Blangero J, Griffiths LR (2012a) A genome-wide analysis of ‘Bounty’ descendants implicates several novel variants in migraine susceptibility. Neurogenetics 13(3):261–266PubMedCentralCrossRefPubMedGoogle Scholar
  13. Cox HC, Lea RA, Bellis C, Nyholt DR, Dyer TD, Haupt LM, Charlesworth J, Matovinovic E, Blangero J, Griffiths LR (2012b) Heritability and genome-wide linkage analysis of migraine in the genetic isolate of Norfolk Island. Gene 494(1):119–123CrossRefPubMedGoogle Scholar
  14. Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AM, Pusch M, Strom TM (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366(9483):371–377CrossRefPubMedGoogle Scholar
  15. Global Burden of Disease Study C (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. LancetGoogle Scholar
  16. International HapMap, C, Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F, Peltonen L, Dermitzakis E, Bonnen PE, Altshuler DM, Gibbs RA, de Bakker PI, Deloukas P, Gabriel SB, Gwilliam R, Hunt S, Inouye M, Jia X, Palotie A, Parkin M, Whittaker P, Yu F, Chang K, Hawes A, Lewis LR, Ren Y, Wheeler D, Gibbs RA, Muzny DM, Barnes C, Darvishi K, Hurles M, Korn JM, Kristiansson K, Lee C, McCarrol SA, Nemesh J, Dermitzakis E, Keinan A, Montgomery SB, Pollack S, Price AL, Soranzo N, Bonnen PE, Gibbs RA, Gonzaga-Jauregui C, Keinan A, Price AL, Yu F, Anttila V, Brodeur W, Daly MJ, Leslie S, McVean G, Moutsianas L, Nguyen H, Schaffner SF, Zhang Q, Ghori MJ, McGinnis R, McLaren W, Pollack S, Price AL, Schaffner SF, Takeuchi F, Grossman SR, Shlyakhter I, Hostetter EB, Sabeti PC, Adebamowo CA, Foster MW, Gordon DR, Licinio J, Manca MC, Marshall PA, Matsuda I, Ngare D, Wang VO, Reddy D, Rotimi CN, Royal CD, Sharp RR, Zeng C, Brooks LD, McEwen JE (2010) Integrating common and rare genetic variation in diverse human populations. Nature 467(7311):52–58CrossRefGoogle Scholar
  17. International Schizophrenia, C, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256):748–752Google Scholar
  18. Jorde LB, Watkins WS, Kere J, Nyman D, Eriksson AW (2000) Gene mapping in isolated populations: new roles for old friends? Hum Hered 50(1):57–65CrossRefPubMedGoogle Scholar
  19. Karolchik D, Hinrichs AS, Furey TS, Roskin KM, Sugnet CW, Haussler D, Kent WJ (2004) The UCSC Table Browser data retrieval tool. Nucleic Acids Res 32(Database issue): D493–D496Google Scholar
  20. Khaitovich P, Muetzel B, She X, Lachmann M, Hellmann I, Dietzsch J, Steigele S, Do HH, Weiss G, Enard W, Heissig F, Arendt T, Nieselt-Struwe K, Eichler EE, Paabo S (2004) Regional patterns of gene expression in human and chimpanzee brains. Genome Res 14(8):1462–1473PubMedCentralCrossRefPubMedGoogle Scholar
  21. Levin M (2013) The International classification of headache disorders, 3rd edition (ICHD III)—changes and challenges. Headache 53(8):1383–1395CrossRefGoogle Scholar
  22. Ligthart L, de Vries B, Smith AV, Ikram MA, Amin N, Hottenga JJ, Koelewijn SC, Kattenberg VM, de Moor MH, Janssens AC, Aulchenko YS, Oostra BA, de Geus EJ, Smit JH, Zitman FG, Uitterlinden AG, Hofman A, Willemsen G, Nyholt DR, Montgomery GW, Terwindt GM, Gudnason V, Penninx BW, Breteler M, Ferrari MD, Launer LJ, van Duijn CM, van den Maagdenberg AM, Boomsma DI (2011) Meta-analysis of genome-wide association for migraine in six population-based European cohorts. Eur J Hum Genet 19(8):901–907PubMedCentralCrossRefPubMedGoogle Scholar
  23. Liu C (2011) Brain expression quantitative trait locus mapping informs genetic studies of psychiatric diseases. Neurosci Bull 27(2):123–133PubMedCentralCrossRefPubMedGoogle Scholar
  24. Maher BH, Lea RA, Benton M, Cox HC, Bellis C, Carless M, Dyer TD, Curran J, Charlesworth JC, Buring JE, Kurth T, Chasman DI, Ridker PM, Schurks M, Blangero J, Griffiths LR (2012) An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12. PLoS ONE 7(5):e37903PubMedCentralCrossRefPubMedGoogle Scholar
  25. McKenzie M, Henders AK, Caracella A, Wray NR, Powell JE (2014) Overlap of expression quantitative trait loci (eQTL) in human brain and blood. BMC Med Genom 7:31CrossRefGoogle Scholar
  26. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215PubMedCentralCrossRefPubMedGoogle Scholar
  27. Morrison AC, Bare LA, Chambless LE, Ellis SG, Malloy M, Kane JP, Pankow JS, Devlin JJ, Willerson JT, Boerwinkle E (2007) Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 166(1):28–35CrossRefPubMedGoogle Scholar
  28. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 + channel gene CACNL1A4. Cell 87(3):543–552CrossRefPubMedGoogle Scholar
  29. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575PubMedCentralCrossRefPubMedGoogle Scholar
  30. Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, Bergen SE, Collins AL, Crowley JJ, Fromer M, Kim Y, Lee SH, Magnusson PK, Sanchez N, Stahl EA, Williams S, Wray NR, Xia K, Bettella F, Borglum AD, Bulik-Sullivan BK, Cormican P, Craddock N, de Leeuw C, Durmishi N, Gill M, Golimbet V, Hamshere ML, Holmans P, Hougaard DM, Kendler KS, Lin K, Morris DW, Mors O, Mortensen PB, Neale BM, O’Neill FA, Owen MJ, Milovancevic MP, Posthuma D, Powell J, Richards AL, Riley BP, Ruderfer D, Rujescu D, Sigurdsson E, Silagadze T, Smit AB, Stefansson H, Steinberg S, Suvisaari J, Tosato S, Verhage M, Walters JT, C. Multicenter Genetic Studies of Schizophrenia, Levinson DF, Gejman PV, Kendler KS, Laurent C, Mowry BJ, O’Donovan MC, Owen MJ, Pulver AE, Riley BP, Schwab SG, Wildenauer DB, Dudbridge F, Holmans P, Shi J, Albus M, Alexander M, Campion D, Cohen D, Dikeos D, Duan J, Eichhammer P, Godard S, Hansen M, Lerer FB, Liang KY, Maier W, Mallet J, Nertney DA, Nestadt G, Norton N, O’Neill FA, Papadimitriou GN, Ribble R, Sanders AR, Silverman JM, Walsh D, Williams NM, Wormley B, C. Psychosis Endophenotypes International, Arranz MJ, Bakker S, Bender S, Bramon E, Collier D, Crespo-Facorro B, Hall J, Iyegbe C, Jablensky A, Kahn RS, Kalaydjieva L, Lawrie S, Lewis CM, Lin K, Linszen DH, Mata I, McIntosh A, Murray RM, Ophoff RA, Powell J, Rujescu D, Van Os J, Walshe M, Weisbrod M, Wiersma D, C. Wellcome Trust Case Control, Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin AP, Deloukas P, Duncanson A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Spencer CC, Band G, Bellenguez C, Freeman C, Hellenthal G, Giannoulatou E, Pirinen M, Pearson RD, Strange A, Su Z, Vukcevic D, Donnelly P, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Potter SC, Ravindrarajah R, Ricketts M, Tashakkori-Ghanbaria A, Waller MJ, Weston P, Widaa S, Whittaker P, Barroso I, Deloukas P, Mathew CG, Blackwell JM, Brown MA, Corvin AP, McCarthy MI, Spencer CC, Bramon E, Corvin AP, O’Donovan MC, Stefansson K, Scolnick E, Purcell S, McCarroll SA, Sklar P, Hultman CM, Sullivan PF (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45(10):1150–1159CrossRefPubMedGoogle Scholar
  31. Rodriguez-Acevedo AJ, Maher BH, Lea RA, Benton M, Griffiths LR (2013) Association of oestrogen-receptor gene (ESR1) polymorphisms with migraine in the large Norfolk Island pedigree. Cephalalgia 33(14):1139–1147CrossRefPubMedGoogle Scholar
  32. Safran M, Dalah I, Alexander J, Rosen N, Iny Stein T, Shmoish M, Nativ N, Bahir I, Doniger T, Krug H, Sirota-Madi A, Olender T, Golan Y, Stelzer G, Harel A, Lancet D (2010) GeneCards Version 3: the human gene integrator. Database (v2010)Google Scholar
  33. Seifuddin F, Pirooznia M, Judy JT, Goes FS, Potash JB, Zandi PP (2013) Systematic review of genome-wide gene expression studies of bipolar disorder. BMC Psychiatry 13:213PubMedCentralCrossRefPubMedGoogle Scholar
  34. Silberstein SD, Dodick DW (2013) Migraine genetics: part II. Headache 53(8):1218–1229CrossRefPubMedGoogle Scholar
  35. Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, Beazley C, Ingle CE, Dunning M, Flicek P, Koller D, Montgomery S, Tavare S, Deloukas P, Dermitzakis ET (2007) Population genomics of human gene expression. Nat Genet 39(10):1217–1224PubMedCentralCrossRefPubMedGoogle Scholar
  36. Stuart S, Maher BH, Sutherland H, Benton M, Rodriguez A, Lea RA, Haupt LM, Griffiths LR (2013) Genetic variation in cytokine-related genes and migraine susceptibility. Twin Res Hum Genet 16(6):1079–1086CrossRefPubMedGoogle Scholar
  37. Vawter MP, Atz ME, Rollins BL, Cooper-Casey KM, Shao L, Byerley WF (2006) Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia. Hum Genet 119(5):558–570PubMedCentralCrossRefPubMedGoogle Scholar
  38. Veyrieras JB, Kudaravalli S, Kim SY, Dermitzakis ET, Gilad Y, Stephens M, Pritchard JK (2008) High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet 4(10):e1000214PubMedCentralCrossRefPubMedGoogle Scholar
  39. Wang YP, Qi ML, Li TT, Zhao YJ (2012) Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD). Gene 498(1):112–115CrossRefPubMedGoogle Scholar
  40. Westra H-J, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, Zhernakova A, Zhernakova DV, Veldink JH, Van den Berg LH, Karjalainen J, Withoff S, Uitterlinden AG, Hofman A, Rivadeneira F, t Hoen PAC, Reinmaa E, Fischer K, Nelis M, Milani L, Melzer D, Ferrucci L, Singleton AB, Hernandez DG, Nalls MA, Homuth G, Nauck M, Radke D, Volker U, Perola M, Salomaa V, Brody J, Suchy-Dicey A, Gharib SA, Enquobahrie DA, Lumley T, Montgomery GW, Makino S, Prokisch H, Herder C, Roden M, Grallert H, Meitinger T, Strauch K, Li Y, Jansen RC, Visscher PM, Knight JC, Psaty BM, Ripatti S, Teumer A, Frayling TM, Metspalu A, van Meurs JBJ, Franke L (2013) Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45(10):1238–1243PubMedCentralCrossRefPubMedGoogle Scholar
  41. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, Madden PA, Heath AC, Martin NG, Montgomery GW, Goddard ME, Visscher PM (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42(7):565–569PubMedCentralCrossRefPubMedGoogle Scholar
  42. Zeller T, Wild P, Szymczak S, Rotival M, Schillert A, Castagne R, Maouche S, Germain M, Lackner K, Rossmann H, Eleftheriadis M, Sinning CR, Schnabel RB, Lubos E, Mennerich D, Rust W, Perret C, Proust C, Nicaud V, Loscalzo J, Hubner N, Tregouet D, Munzel T, Ziegler A, Tiret L, Blankenberg S, Cambien F (2010) Genetics and beyond–the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5(5):e10693PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • A. J. Rodriguez-Acevedo
    • 1
  • M. A. Ferreira
    • 2
  • Miles C. Benton
    • 1
  • Melanie A. Carless
    • 3
  • Harald H. Goring
    • 4
  • Joanne E. Curran
    • 4
  • John Blangero
    • 4
  • R. A. Lea
    • 1
  • L. R. Griffiths
    • 1
    Email author
  1. 1.Genomics Research Centre, Institute of Health and Biomedical InnovationQUTBrisbaneAustralia
  2. 2.QIMR-Berghofer Medical Research InstituteBrisbaneAustralia
  3. 3.Texas Biomedical Research InstituteSan AntonioUSA
  4. 4.South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineBrownsvilleUSA

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