Using Phenotypic Heterogeneity to Increase the Power of Genome-Wide Association Studies: Application to Age at Onset of Ischaemic Stroke Subphenotypes

Genetic Epidemiology

Volumn 37, Issue 5, 2013, Pages 495-503

  Traylor, Matthew ^a   Bevan, Steve ^a   Rothwell, Peter M ^b   Sudlow, Cathie ^c   Dichgans, Martin ^d   Markus, Hugh S ^a   Lewis, Cathryn M ^e  

^a ST GEORGE'S UNIVERSITY OF LONDON   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c UNIVERSITY OF EDINBURGH   (United Kingdom)

^d LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^e KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Age at onset; Genome wide association study; Heterogeneity; Ischaemic stroke

Indexed keywords

ADULT; AGED; ARTICLE; BRAIN ISCHEMIA; CARDIOEMBOLIC STROKE; FEMALE; GENETIC ASSOCIATION; GENETIC HETEROGENEITY; GENETIC PREDISPOSITION; GENETIC SCREENING; GENOTYPE; GENOTYPE PHENOTYPE CORRELATION; GERMANY; HUMAN; MAJOR CLINICAL STUDY; MALE; ONSET AGE; PHENOTYPE; PHENOTYPIC VARIATION; SINGLE NUCLEOTIDE POLYMORPHISM; UNITED KINGDOM;

AGE OF ONSET; AGED; AGED, 80 AND OVER; BRAIN ISCHEMIA; CASE-CONTROL STUDIES; FEMALE; GENOME-WIDE ASSOCIATION STUDY; GERMANY; GREAT BRITAIN; HUMANS; MALE; MIDDLE AGED; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE; STROKE;

EID: 84879182211     PISSN: 07410395     EISSN: 10982272     Source Type: Journal    
DOI: 10.1002/gepi.21729     Document Type: Article

References (45)

1. Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd. 1993. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35-41.
2. Bak S, Gaist D, Sindrup SH, Skytthe A, Christensen K. 2002. Genetic liability in stroke: a long-term follow up study of Danish twins. Stroke 33:769-774.
3. Bevan S, Traylor M, Adib-Samii P, Malik R, Paul NL, Jackson C, Farrall M, Rothwell PM, Sudlow C, Dichgans M and others. 2012. Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations. Stroke 43:3161-3167.
4. Bradfield JP, Taal HR, Timpson NJ, Scherag A, Lecoeur C, Warrington NM, Hypponen E, Holst C, Valcarcel B, Thiering E and others. 2012. A genome-wide association meta-analysis identifies new childhood obesity loci. Nat Genet 44:526-531.
5. Brass LM, Isaacsohn JL, Merikangas KR, Robinette CD. 1992. A study of twins and stroke. Stroke 23:221-3.
6. Cheng YC, O'Connell JR, Cole JW, Stine OC, Dueker N, McArdle PF, Sparks MJ, Shen J, Laurie CC, Nelson S and others. 2011. Genome-wide association analysis of ischemic stroke in young adults. G3 (Bethesda) 1:505-514.
7. Dichgans M. 2007. Genetics of ischaemic stroke. Lancet Neurol 6:149-161.
8. Fisher CM. 1982. Lacunar strokes and infarcts: a review. Neurology 32:871-876.
9. Flossman E, Rothwell PM. 2004. Systematic review of methods and results of studies of the genetic epidemiology of ischaemic stroke. Stroke 35:212-227.
10. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R and others. 2010. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42:1118-1125.
11. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Bousser MG, Heutink P, Miner JH, Tournier-Lasserve E and others. 2006. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 354:1489-1496.
12. Gretarsdottir S, Thorleifsson G, Manolescu A, Styrkarsdottir U, Helgadottir A, Gschwendtner A, Kostulas K, Kuhlenbäumer G, Bevan S, Jonsdottir T and others. 2008. Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol 64:402-409.
13. Gschwendtner A, Bevan S, Cole JW, Plourde A, Matarin M, Ross-Adams H, Meitinger T, Wichmann E, Mitchell BD, Furie K and others. 2009. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol 65:531-539.
14. Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB, Thorgeirsson G, Gulcher J, Mathiesen EB, Njølstad I, Nyrnes A and others. 2009. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 41:876-878.
15. Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, Kawata H, Koyama A, Arima K, Takahashi T and others. 2009. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 360:1729-1739.
16. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA. 2009. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106:9362-9367.
17. Holliday EG, Maguire JM, Evans TJ, Koblar SA, Jannes J, Sturm JW, Hankey GJ, Baker R, Golledge J, Parsons MW and others. 2012. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nat Genet 44:1147-1151.
18. Imielinski M, Baldassano RN, Griffiths A, Russell RK, Annese V, Dubinsky M, Kugathasan S, Bradfield JP, Walters TD, Sleiman P and others. 2009. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 41:1335-1340.
19. International Stroke Genetics Consortium (ISGC), Wellcome Trust Case Control Consortium 2 (WTCCC2), Bellenguez C, Bevan S, Gschwendtner A, Spencer CC, Burgess AI, Pirinen M, Jackson CA, Traylor M and others. 2012. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet 44:328-333.
20. Jood K, Ladenvall C, Rosengren A, Blomstrand C, Jern C. 2005. Family history in ischemic stroke before 70 years of age: the Sahlgrenska Academy Study on Ischemic Stroke. Stroke 36:1383-1387.
21. Jerrard-Dunne P, Cloud G, Hassan A, Markus HS. 2003. Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke 34:1364-1369.
22. Khan U, Porteous L, Hassan A, Markus HS. 2007. Risk factor profile of cerebral small vessel disease and its subtypes. J Neurol Neurosurg Psychiatry 78:702-706.
23. Lee SH, DeCandia TR, Ripke S, Yang J, Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), International Schizophrenia Consortium (ISC), Molecular Genetics of Schizophrenia Collaboration (MGS), Sullivan PF, Goddard ME, Keller MC and others. 2012. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 44:247-250.
24. Li Y, Sheu CC, Ye Y, de Andrade M, Wang L, Chang SC, Aubry MC, Aakre JA, Allen MS, Chen F. 2010. Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet Oncol 11:321-330.
25. MacClellan LR, Mitchell BD, Cole JW, Wozniak MA, Stern BJ, Giles WH, Brown DW, Sparks MJ, Kittner SJ. 2006. Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study. Genet Epidemiol 30:602-608.
26. Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Ripke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, Breen G, Byrne EM, Blackwood DH, Boomsma DI and others. 2013. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18:497-511.
27. Markus HS. 2011. Stroke genetics. Hum Mol Genet 20:R124-R131.
28. Meschia JF, Singleton A, Nalls MA, Rich SS, Sharma P, Ferrucci L, Matarin M, Hernandez DG, Pearce K, Brott TG and others. 2011. Genomic risk profiling of ischemic stroke: results of an international genome-wide association meta-analysis. PLoS One 6:e23161.
29. Myocardial Infarction Genetics Consortium, Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Samani NJ and others. 2009. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 41:334-341.
30. O'Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ and others. 2010. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 376:112-123.
31. Perry JR, Voight BF, Yengo L, Amin N, Dupuis J, Ganser M, Grallert H, Navarro P, Li M, Qi L and others. 2012. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genet 8:e1002741.
32. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. 2006. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904-909.
33. Purcell S, Cherny SS, Sham PC. 2003. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149-150.
34. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ and others. 2007. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559-575.
35. Schulz UGR, Flossmann E, Rothwell PM. 2004. Heritability of ischaemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke 35:819-824.
36. Simonson MA, Wills AG, Keller MC, McQueen MB. 2011. Recent methods for polygenic analysis of genome-wide data implicate an important effect of common variants on cardiovascular disease risk. BMC Med Genet 12:146.
37. Steemers FJ, Gunderson KL. 2007. Whole genome genotyping technologies on the BeadArray platform. Biotechnol J 2:41-49.
38. The DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Morris AP, Voight BF, Teslovich TM, Ferreira T, Segré AV, Steinthorsdottir V, Strawbridge RJ, Khan H, Grallert H and others. 2012. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44:981-990.
39. Thompson SD, Marion MC, Sudman M, Ryan M, Tsoras M, Howard TD, Barnes MG, Ramos PS, Thomson W, Hinks A and others. 2012. Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. Arthritis Rheum 64:2781-2791.
40. Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J and others. 1993. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 3:256-259.
41. Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng YC, Fornage M, Ikram MA, Malik R, Bevan S and others. 2012. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide associated studies. Lancet Neurol 11:951-962.
42. Visscher PM, Brown MA, McCarthy MI, Yang J. 2012. Five years of GWAS discovery. Am J Hum Genet 90:7-24.
43. Willer CJ, Li Y, Abecasis GR. 2010. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190-2191.
44. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, Madden PA, Heath AC, Martin NG, Montgomery GW and others. 2010. Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42:565-569.
45. Yang J, Lee SH, Goddard ME, Visscher PM. 2011. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88:76-82.