Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

D.I. Boomsma; L. Ligthart; Danielle Posthuma; 23Andme Research Team

doi:10.1016/j.neuron.2018.04.014

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

D.I. Boomsma, L. Ligthart, Danielle Posthuma, 23Andme Research Team

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Abstract

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71–1.81, p = 1.7 × 10 ⁻¹⁰⁹ ) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25–1.38, p = 7.2 × 10 ⁻¹⁷ ). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine. Gormley et al. use polygenic risk scores to show that common variation, captured by genome-wide association studies, in combination contributes to the aggregation of migraine in families. The results may have similar implications for other complex traits in general.

Original language	English
Pages (from-to)	743-753.e4
Journal	Neuron
Volume	98
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2018.04.014
Publication status	Published - 16 May 2018

Funding

This work was supported by the Wellcome Trust (grant numbers WT089062 , 098051 to A.P.); the Academy of Finland (grant numbers 286500 , 293404 to A.P., and 139795 to M.W.); the Academy of Finland Center of Excellence for Complex Disease Genetics (grant number 312074 ); the EuroHead project ( LSM-CT-2004-504837 to A.P.); FP7-EUROHEADPAIN (grant number 602633 to A.P.); ENGAGE Consortium (grant agreement HEALTH-F4-2007-201413 to A.P.); EU/SYNSYS-Synaptic Systems (grant number 242167 to A.P.); the Sigrid Juselius Foundation, Finland (to A.P.); the Nordic Information for Action eScience Center, NIASC (Grant No 62721 to A.P.); NIH /Genomic strategies to identify high-impact psychiatric risk variants (Grant No 1U01MH105666-01 to A.P.); the Folkh\u00E4lsan Research Foundation, Finland (to M.W.); Medicinska Underst\u00F6dsf\u00F6reningen Liv & H\u00E4lsa, Finland (to M.W.); the Helsinki University Central Hospital (to M.K., M.F., V.A.); the Swedish Research Foundation (grant number 2017-01096 to A.C.B.); the Swedish Brain Foundation (to A.C.B. and C.R.); and Karolinska Institutet Research Funds (to A.C.B.). T.L. was supported by the Academy of Finland : grants 286284 , 134309 (Eye), 126925 , 121584 , 124282 , 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland ; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001 ); Juho Vainio Foundation ; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research ; Finnish Cultural Foundation ; Tampere Tuberculosis Foundation ; Emil Aaltonen Foundation ; Yrj\u00F6 Jahnsson Foundation ; Signe and Ane Gyllenberg Foundation ; Diabetes Research Foundation of Finnish Diabetes Association ; and EU Horizon 2020 (grant 755320 for TAXINOMISIS). The work was further supported by funding from Merck and Co. , Kenilworth, NJ, USA. We would like to thank the participants of the NFBC1966 study and the NFBC project center. We are sincerely grateful to all members of the Finnish migraine families for participating in this research. We would also like to thank the research participants and employees of 23andMe, Inc., a personal genetics company, for making this work possible. The study was partially funded by Merck and Co., Kenilworth, NJ, USA. Members of the 23andMe Research Team are current or former employees of 23andMe, Inc. and hold stock or stock options in 23andMe.

Funders	Funder number
Academy of Finland Center of Excellence for Complex Disease Genetics	LSM-CT-2004-504837, 312074, FP7-EUROHEADPAIN, 602633
ENGAGE Consortium	HEALTH-F4-2007-201413
EU/SYNSYS-Synaptic Systems	242167
Medicinska Understödsföreningen Liv & Hälsa, Finland
Merck and Co.
NIASC	62721
Nordic Information for Action eScience Center
National Institutes of Health
National Institute of Mental Health	U01MH105666
Merck
Helsingin ja Uudenmaan Sairaanhoitopiiri
Yrjö Jahnssonin Säätiö
Wellcome Trust	WT089062, 098051
Folkhälsanin Tutkimussäätiö
Swedish Foundation for MS Research	2017-01096
Academy of Finland	293404, 286500, 139795
Suomen Kulttuurirahasto
Hjärnfonden
Juho Vainion Säätiö
Karolinska Institutet	126925, 121584, 129378, 117787, 134309, 286284, 41071, 124282
Signe ja Ane Gyllenbergin Säätiö
Emil Aaltosen Säätiö
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
Tampereen Tuberkuloosisäätiö
Horizon 2020	755320
Diabetesliitto
Paavo Nurmen Säätiö
Turun Yliopistollinen Keskussairaala	X51001

Keywords

disease aggregation
familial aggregation
families
genome-wide association study
GWAS
hemiplegic migraine
migraine
migraine with aura
polygenic risk score
PRS

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neuron.2018.04.014

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 FamiliesFinal published version, 1.42 MBLicence: Article 25fa Dutch Copyright Act

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title = "Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families",

abstract = "Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95\% CI = 1.71–1.81, p = 1.7 × 10 −109 ) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95\% CI = 1.25–1.38, p = 7.2 × 10 −17 ). The PRS explained 1.6\% of the phenotypic variance in the population cases and 3.5\% in the familial cases (including 2.9\% for migraine without aura, 5.5\% for migraine with typical aura, and 8.2\% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine. Gormley et al. use polygenic risk scores to show that common variation, captured by genome-wide association studies, in combination contributes to the aggregation of migraine in families. The results may have similar implications for other complex traits in general. ",

keywords = "disease aggregation, familial aggregation, families, genome-wide association study, GWAS, hemiplegic migraine, migraine, migraine with aura, polygenic risk score, PRS",

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AU - Veerapen, Kumar

AU - Häppölä, Paavo

AU - Mitchell, Adele A

AU - Lal, Dennis

AU - Palta, Priit

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AU - Kaunisto, Mari Anneli

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AU - Ilmavirta, Matti

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AU - Säkö, Erkki

AU - Sumelahti, Marja-Liisa

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AU - Palotie, Aarno

AU - Boomsma, D.I.

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AU - Posthuma, Danielle

AU - 23Andme Research Team

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Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

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Keywords

Cohort Studies

UN SDGs

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