Common variant burden contributes significantly to the familial aggregation of migraine in 1,589 families
Common variant burden contributes significantly to the familial aggregation of migraine in 1,589 families
Abstract It has long been observed that complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. Two competing hypotheses exist, emphasizing either rare or common genetic variation. More specifically, familial aggregation could be predominantly explained by rare, penetrant variants that segregate according to Mendelian inheritance or rather by the sufficient polygenic accumulation of many common variants, each with an individually small effect. Some combination of both common and rare variation could also contribute towards a spectrum of disease risk. We investigated this in a collection of 8,319 individuals across 1,589 migraine families from Finland. Family members were individually diagnosed by a migraine-specific questionnaire with either migraine without aura (MO, ICHD-3 code 1.1, n=2,357), migraine with typical aura (ICHD- 3 code 1.2.1, n=2,420), hemiplegic migraine (HM, ICHD-3 code 1.2.3, n=540), or no migraine (n=3,002). For comparison, we used population-based migraine cases (n=1,101) and controls (n=13,369) from the FINRISK study. The disease status of FINRISK individuals was assigned based on health registry data from outpatient clinics and/or prescription medication. All individuals were genotyped on the Illumina? CoreExome or PsychArray chip platforms and imputed to a Finnish reference panel of 6,962 haplotypes. Polygenic risk scores (PRS), representing the common variant burden in each individual, were calculated using weights from the most recent large-scale genome-wide association study of migraine. To account for family structure in our analyses, we used a mixed-model approach, adjusting for the genetic relationship matrix as a random effect. We found a significantly higher common variant burden in familial cases of migraine (for all subtypes, measured by the odds ratio [OR] per standard deviation [SD] increase in PRS; OR = 1.76, 95% CI = 1.71-1.81, P = 1.7×10?109) compared to cases from a population cohort (OR = 1.32, 95% CI = 1.25-1.38, P = 7.2×10?17) when using the population controls as a reference group. The highest enrichment was observed for HM (OR = 1.96, 95% CI = 1.86-2.07, P = 8.7×10?36) and migraine with typical aura (OR = 1.85, 95% CI = 1.79-1.91, P = 1.4×10?86) but enrichment was also present for MO (OR = 1.57, 95% CI = 1.51-1.63, P = 1.1×10?48). Comparing within cases, there was no significant difference in common variant burden between the migraine with aura subtypes, HM and migraine with typical aura (OR = 1.09, 95% CI = 0.99-1.19, P = 0.09), but both showed significantly higher enrichment compared to MO (OR = 1.28, 95% CI = 1.17-1.38, P = 7.3×10?7, and OR = 1.17, 95% CI = 1.11-1.23, P = 4.62×10?5, respectively). Additionally, we found that higher common variant burden corresponded to earlier age of headache onset (OR per SD increase in PRS for 3,631 cases with onset before 20 years old compared to 1,686 cases with onset later than 20 years old; OR = 1.11, 95% CI = 1.05-1.18, P = 8.3×10?4). FINRISK population cases identified from national health registry data were found to have lower common variant burden in comparison to the familial migraine cases (OR = 1.32, 95% CI = 1.25-1.38, P = 6.8×10?17), unless the individuals had attended both a specialist clinic and also received prophylactic migraine treatment (OR = 1.70, 95% CI = 1.53-1.88, P = 3.9×10?9). Finally, although rare variants have been suggested as the primary cause for familial hemiplegic migraine (FHM), we found only four out of 45 sequenced FHM families (8.9%) with a pathogenic mutation in one of the known risk genes. In summary, our results demonstrate a substantial contribution of common polygenic variation to familial aggregation in migraine, comparable to both controls and that observed in migraine cases from a population cohort. The findings also suggest that individuals with migraine aura symptoms (either typical aura, which is mostly visual, or rare motor aura) tend to have higher common variant burden on average supporting the polygenic model also in these migraine subtypes.
Sumelahti M-L.、Mitchell A.、Palotie A.、H?m?l?inen E.、Havanka H.、Anttila V.、F?rkkil? M.、Daly M.J.、Neale B.M.、Kallela M.、Wessman M.、Kurki M.I.、S?k? E.、Ilmavirta M.、Veerapen K.、Artto V.、Gormley P.、Salomaa V、23andMe Research Team、Runz H.、Ripatti S.、Hiekkala M.E.、Palta P.、The International Headache Genetics Consortium (IHGC)、Kaunisto M.A.、Mets?honkala L.、Harno H.、Liukkonen J.、Sillanp?? M.、Nissil? M.、Veps?l?inen S.、Jousilahti P.、H?pp?l? P.、Surakka I.、Lal D.
TerveystaloMerck Research Laboratories, Merck and Co.Massachusetts General Hospital||Harvard Medical School||Broad Institute of MIT and Harvard||Institute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiRegional State Administrative Agency for Northern FinlandMassachusetts General Hospital||Harvard Medical School||Broad Institute of MIT and Harvard||Institute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiDepartment of Neurology, Helsinki University Central HospitalMassachusetts General Hospital||Harvard Medical School||Broad Institute of MIT and HarvardMassachusetts General Hospital||Harvard Medical School||Broad Institute of MIT and HarvardDepartment of Neurology, Helsinki University Central HospitalInstitute of Genetics, Folkh?lsan Research Center||Institute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiMassachusetts General Hospital||Harvard Medical School||Broad Institute of MIT and HarvardTurku Headache CenterDepartment of Neurology, Central Hospital Central FinlandMassachusetts General Hospital||Harvard Medical School||Broad Institute of MIT and HarvardDepartment of Neurology, Helsinki University Central HospitalMassachusetts General Hospital||Harvard Medical School||Broad Institute of MIT and HarvardNational Institute for Health and Welfare23andMe, Inc.Merck Research Laboratories, Merck and Co.Institute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiInstitute of Genetics, Folkh?lsan Research CenterInstitute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiA full list of members and affiliations appears in the Supplementary InformationInstitute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiEpilepsy Unit for Children and Adolescents, Helsinki University HospitalNeurology, Clinical Neurosciences, University of Helsinki and Helsinki University HospitalL??k?rikeskus IkiomaDepartments of Child Neurology and General Practice, University of Turku, and Turku University HospitalTerveystalo Clinical ResearchDepartment of Neurology, Helsinki University Central HospitalNational Institute for Health and WelfareInstitute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland FIMM, HiLIFE, University of HelsinkiMassachusetts General Hospital||Harvard Medical School||Broad Institute of MIT and Harvard||Cologne Center for Genomics, University of Cologne
神经病学、精神病学医学研究方法基础医学
Sumelahti M-L.,Mitchell A.,Palotie A.,H?m?l?inen E.,Havanka H.,Anttila V.,F?rkkil? M.,Daly M.J.,Neale B.M.,Kallela M.,Wessman M.,Kurki M.I.,S?k? E.,Ilmavirta M.,Veerapen K.,Artto V.,Gormley P.,Salomaa V,23andMe Research Team,Runz H.,Ripatti S.,Hiekkala M.E.,Palta P.,The International Headache Genetics Consortium (IHGC),Kaunisto M.A.,Mets?honkala L.,Harno H.,Liukkonen J.,Sillanp?? M.,Nissil? M.,Veps?l?inen S.,Jousilahti P.,H?pp?l? P.,Surakka I.,Lal D..Common variant burden contributes significantly to the familial aggregation of migraine in 1,589 families[EB/OL].(2025-03-28)[2025-07-17].https://www.biorxiv.org/content/10.1101/226985.点此复制
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