. 2018 May 16;98(4):743-753.e4.

doi: 10.1016/j.neuron.2018.04.014. Epub 2018 May 3.

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

Padhraig Gormley¹, Mitja I Kurki¹, Marjo Eveliina Hiekkala², Kumar Veerapen¹, Paavo Häppölä³, Adele A Mitchell⁴, Dennis Lal⁵, Priit Palta³, Ida Surakka³, Mari Anneli Kaunisto³, Eija Hämäläinen³, Salli Vepsäläinen⁶, Hannele Havanka⁷, Hanna Harno⁸, Matti Ilmavirta⁹, Markku Nissilä¹⁰, Erkki Säkö¹¹, Marja-Liisa Sumelahti¹², Jarmo Liukkonen¹³, Matti Sillanpää¹⁴, Liisa Metsähonkala¹⁵, Seppo Koskinen¹⁶, Terho Lehtimäki¹⁷, Olli Raitakari¹⁸, Minna Männikkö¹⁹, Caroline Ran²⁰, Andrea Carmine Belin²⁰, Pekka Jousilahti¹⁶, Verneri Anttila²¹, Veikko Salomaa¹⁶, Ville Artto⁶, Markus Färkkilä⁶; 23andMe Research Team²²; International Headache Genetics Consortium (IHGC); Heiko Runz⁴, Mark J Daly²¹, Benjamin M Neale¹, Samuli Ripatti²³, Mikko Kallela⁶, Maija Wessman²⁴, Aarno Palotie²⁵

Collaborators, Affiliations

Collaborators

Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, Karen E Huber, Aaron Kleinman, Nadia K Litterman, Jennifer C McCreight, Matthew H McIntyre, Joanna L Mountain, Carrie A M Northover, Steven J Pitts, J Fah Sathirapongsasuti, Olga V Sazonova, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Vladimir Vacic, Catherine H Wilson, Verneri Anttila, Ville Artto, Andrea Carmine Belin, Dorret I Boomsma, Sigrid Børte, Daniel I Chasman, Lynn Cherkas, Anne Francke Christensen, Bru Cormand, Ester Cuenca-Leon, George Davey-Smith, Martin Dichgans, Cornelia van Duijn, Tonu Esko, Ann-Louise Esserlind, Michel D Ferrari, Rune R Frants, Tobias Freilinger, Nick Furlotte, Padhraig Gormley, Lyn Griffiths, Eija Hamalainen, Thomas Folkmann Hansen, Marjo Hiekkala, M Arfan Ikram, Andres Ingason, Marjo-Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Christian Kubisch, Mitja Kurki, Tobias Kurth, Lenore Launer, Terho Lehtimaki, Davor Lessel, Lannie Ligthart, Nadia Litterman, Arn van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Muller-Myhsok, Benjamin M Neale, Carrie Northover, Dale R Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda Pedersen, Nancy Pedersen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Lydia Quaye, Olli Raitakari, Markus Schürks, Celia Sintas, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, David Strachan, Gisela Terwindt, Marta Vila-Pueyo, Maija Wessman, Bendik S Winsvold, William Wrenthal, Huiying Zhao, John-Anker Zwart

Affiliations

¹ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁴ Merck Research Laboratories, Merck and Co., Kenilworth, NJ, USA.
⁵ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁶ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
⁷ Regional State Administrative Agency for Northern Finland, Oulu, Finland.
⁸ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland; Division of Pain Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Finland.
⁹ Department of Neurology, Central Hospital Central Finland, Jyväskylä.
¹⁰ Terveystalo Clinical Research, Turku, Finland.
¹¹ Turku Headache Center, Turku, Finland.
¹² Terveystalo, Tampere, Finland.
¹³ Lääkärikeskus Ikioma, Mikkeli, Finland.
¹⁴ Departments of Child Neurology and General Practice, University of Turku, and Turku University Hospital, Turku, Finland.
¹⁵ Epilepsy Unit for Children and Adolescents, Helsinki University Hospital, Helsinki, Finland.
¹⁶ National Institute for Health and Welfare, Helsinki, Finland.
¹⁷ Department of Clinical Chemistry, Fimlab Laboratories, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
¹⁸ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
¹⁹ Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.
²⁰ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
²¹ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
²² 23andMe, Inc., Mountain View, CA, USA.
²³ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Public Health, Faculty of Medicine, University of Helsinki, Finland.
²⁴ Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
²⁵ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. Electronic address: aarno.palotie@helsinki.fi.

PMID: 29731251
PMCID: PMC5967411
DOI: 10.1016/j.neuron.2018.04.014

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

Padhraig Gormley et al. Neuron. 2018.

. 2018 May 16;98(4):743-753.e4.

doi: 10.1016/j.neuron.2018.04.014. Epub 2018 May 3.

Authors

Collaborators

Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, Karen E Huber, Aaron Kleinman, Nadia K Litterman, Jennifer C McCreight, Matthew H McIntyre, Joanna L Mountain, Carrie A M Northover, Steven J Pitts, J Fah Sathirapongsasuti, Olga V Sazonova, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Vladimir Vacic, Catherine H Wilson, Verneri Anttila, Ville Artto, Andrea Carmine Belin, Dorret I Boomsma, Sigrid Børte, Daniel I Chasman, Lynn Cherkas, Anne Francke Christensen, Bru Cormand, Ester Cuenca-Leon, George Davey-Smith, Martin Dichgans, Cornelia van Duijn, Tonu Esko, Ann-Louise Esserlind, Michel D Ferrari, Rune R Frants, Tobias Freilinger, Nick Furlotte, Padhraig Gormley, Lyn Griffiths, Eija Hamalainen, Thomas Folkmann Hansen, Marjo Hiekkala, M Arfan Ikram, Andres Ingason, Marjo-Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Christian Kubisch, Mitja Kurki, Tobias Kurth, Lenore Launer, Terho Lehtimaki, Davor Lessel, Lannie Ligthart, Nadia Litterman, Arn van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Muller-Myhsok, Benjamin M Neale, Carrie Northover, Dale R Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda Pedersen, Nancy Pedersen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Lydia Quaye, Olli Raitakari, Markus Schürks, Celia Sintas, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, David Strachan, Gisela Terwindt, Marta Vila-Pueyo, Maija Wessman, Bendik S Winsvold, William Wrenthal, Huiying Zhao, John-Anker Zwart

Affiliations

¹ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁴ Merck Research Laboratories, Merck and Co., Kenilworth, NJ, USA.
⁵ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁶ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
⁷ Regional State Administrative Agency for Northern Finland, Oulu, Finland.
⁸ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland; Division of Pain Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Finland.
⁹ Department of Neurology, Central Hospital Central Finland, Jyväskylä.
¹⁰ Terveystalo Clinical Research, Turku, Finland.
¹¹ Turku Headache Center, Turku, Finland.
¹² Terveystalo, Tampere, Finland.
¹³ Lääkärikeskus Ikioma, Mikkeli, Finland.
¹⁴ Departments of Child Neurology and General Practice, University of Turku, and Turku University Hospital, Turku, Finland.
¹⁵ Epilepsy Unit for Children and Adolescents, Helsinki University Hospital, Helsinki, Finland.
¹⁶ National Institute for Health and Welfare, Helsinki, Finland.
¹⁷ Department of Clinical Chemistry, Fimlab Laboratories, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
¹⁸ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
¹⁹ Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.
²⁰ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
²¹ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
²² 23andMe, Inc., Mountain View, CA, USA.
²³ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Public Health, Faculty of Medicine, University of Helsinki, Finland.
²⁴ Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
²⁵ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. Electronic address: aarno.palotie@helsinki.fi.

PMID: 29731251
PMCID: PMC5967411
DOI: 10.1016/j.neuron.2018.04.014

Erratum in

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families.
Gormley P, Kurki MI, Hiekkala ME, Veerapen K, Häppölä P, Mitchell AA, Lal D, Palta P, Surakka I, Kaunisto MA, Hämäläinen E, Vepsäläinen S, Havanka H, Harno H, Ilmavirta M, Nissilä M, Säkö E, Sumelahti ML, Liukkonen J, Sillanpää M, Metsähonkala L, Koskinen S, Lehtimäki T, Raitakari O, Männikkö M, Ran C, Belin AC, Jousilahti P, Anttila V, Salomaa V, Artto V, Färkkilä M; 23andMe Research Team; International Headache Genetics Consortium (IHGC); Runz H, Daly MJ, Neale BM, Ripatti S, Kallela M, Wessman M, Palotie A. Gormley P, et al. Neuron. 2018 Sep 5;99(5):1098. doi: 10.1016/j.neuron.2018.08.029. Neuron. 2018. PMID: 30189203 No abstract available.

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.

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

PubMed Disclaimer

Conflict of interest statement

DECLARATION OF INTERESTS

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.

Figures

**Figure 1. Distributions of the migraine polygenic risk scores (PRS) in the FINRISK population and the Finnish migraine families**
For FINRISK, population controls and cases (any migraine subtype) are shown. For the families, family members with no migraine and familial cases (any migraine subtype) are shown. The vertical axis is density of individuals. SD is standard deviation. n is number of individuals.

**Figure 2. Enrichment of polygenic risk scores (PRS) in familial and population cases**
Odds ratios (OR) given are for one standard deviation (SD) increase in PRS compared to 13,369 FINRISK population controls and calculated using a logistic mixed-model adjusted for genetic relatedness, sex, and age. The PRS was calculated using weights from a published migraine genome-wide association study (GWAS, n = 375,000) (Gormley et al., 2016) for an independent set of 38,872 SNPs (GWAS P-value threshold < 0.1). FINRISK population cases include any migraine cases identified from Finnish National Health Registry data. ‘Families’ are individuals from the Finnish Migraine Families collection. n is number of individuals. CIs are confidence intervals.

**Figure 3. Polygenic transmission disequilibrium test (pTDT) in migraine subtypes**
The Finnish migraine families were subset into trios and grouped by disease status of the offspring, making 734 trios for offspring with no migraine and 1,486 trios for offspring with any migraine. Trios were further divided into migraine subtypes, including 727 trios for migraine without aura, 571 trios for migraine with typical aura, and 188 trios for hemiplegic migraine. The horizontal axis shows the pTDT deviation (and 95% confidence intervals) from the mean PRS that would be expected to be transmitted by the parents under the null. N is the number of trios. Groups with significant over-transmission are marked with ‘*’.

**Figure 4. Mean polygenic risk score (PRS) stratified by age of onset of headaches in migraine cases**
The data shows that higher PRS corresponds to earlier age of onset of migraine headache. Means and 95% confidence intervals (CIs) were estimated within the Finnish migraine families using bootstrap resampling (10,000 replicates) within each age of onset bin. n is number of individuals.

See this image and copyright information in PMC

Comment in

Common Grounds for Family Maladies.
Oexle K, Winkelmann J. Oexle K, et al. Neuron. 2018 May 16;98(4):671-672. doi: 10.1016/j.neuron.2018.05.006. Neuron. 2018. PMID: 29772195

References

1. Agarwala V, Flannick J, Sunyaev S, Altshuler D GoT2D Consortium. Evaluating empirical bounds on complex disease genetic architecture. Nat Genet. 2013;45:1418–1427. - PMC - PubMed
1. Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT. Data quality control in genetic case-control association studies. Nat Protoc. 2010;5:1564–1573. - PMC - PubMed
1. Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS, Nyholt DR, Dimas AS, Freilinger T, Müller-Myhsok B, et al. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet. 2010;42:869–873. - PMC - PubMed
1. Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, Kallela M, Malik R, de Vries B, Terwindt G, et al. Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet. 2013;45:912–917. - PMC - PubMed
1. Borodulin K, Vartiainen E, Peltonen M, Jousilahti P, Juolevi A, Laatikainen T, Männistö S, Salomaa V, Sundvall J, Puska P. Forty-year trends in cardiovascular risk factors in Finland. Eur J Public Health. 2015;25:539–546. - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

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Full Text Sources

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