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Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.

TitleShared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.
Publication TypeJournal Article
Year of Publication2015
AuthorsMalik R, Freilinger T, Winsvold BS, Anttila V, Heiden JVander, Traylor M, de Vries B, Holliday EG, Terwindt GM, Sturm J, Bis JC, Hopewell JC, Ferrari MD, Rannikmae K, Wessman M, Kallela M, Kubisch C, Fornage M, Meschia JF, Lehtimäki T, Sudlow C, Clarke R, Chasman DI, Mitchell BD, Maguire J, Kaprio J, Farrall M, Raitakari OT, Kurth T, M Ikram A, Reiner AP, Longstreth WT, Rothwell PM, Strachan DP, Sharma P, Seshadri S, Quaye L, Cherkas L, Schürks M, Rosand J, Ligthart L, Boncoraglio GB, Smith GDavey, van Duijn CM, Stefansson K, Worrall BB, Nyholt DR, Markus HS, van den Maagdenberg AMJM, Cotsapas C, Zwart JA, Palotie A
Secondary AuthorsDichgans M
Corporate AuthorsInternational Headache Genetics Consortium, METASTROKE Collaboration of the International Stroke Genetics Consortium
JournalNeurology
Volume84
Issue21
Pagination2132-45
Date Published2015 May 26
ISSN1526-632X
KeywordsBrain Ischemia, Genome-Wide Association Study, Humans, Migraine with Aura, Migraine without Aura, Stroke
Abstract

OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.

METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.

RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).

CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

DOI10.1212/WNL.0000000000001606
Alternate JournalNeurology
PubMed ID25934857
PubMed Central IDPMC4451048
Grant ListAA13320 / AA / NIAAA NIH HHS / United States
GR069224 / WT_ / Wellcome Trust / United Kingdom
U54 RR020278 / RR / NCRR NIH HHS / United States
AA07728 / AA / NIAAA NIH HHS / United States
085475/B/08/Z / WT_ / Wellcome Trust / United Kingdom
U01HG004436 / HG / NHGRI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
090532/Z/09/Z / WT_ / Wellcome Trust / United Kingdom
UL1RR025005 / RR / NCRR NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
HL‐080467 / HL / NHLBI NIH HHS / United States
K02AA018755 / AA / NIAAA NIH HHS / United States
DA019951 / DA / NIDA NIH HHS / United States
U01 HG 004446 / HG / NHGRI NIH HHS / United States
R01 HL087676 / HL / NHLBI NIH HHS / United States
G1001799 / MRC_ / Medical Research Council / United Kingdom
UL1RR033176 / RR / NCRR NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
R01 NS45012 / NS / NINDS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
092731 / WT_ / Wellcome Trust / United Kingdom
R01 HL073410 / HL / NHLBI NIH HHS / United States
U01 NS069208 / NS / NINDS NIH HHS / United States
G0600331 / MRC_ / Medical Research Council / United Kingdom
095626 / WT_ / Wellcome Trust / United Kingdom
R01HL59367 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
079895 / WT_ / Wellcome Trust / United Kingdom
Z01 AG-000015-50 / AG / NIA NIH HHS / United States
AA13321 / AA / NIAAA NIH HHS / United States
AA‐12502 / AA / NIAAA NIH HHS / United States
AG-15928 / AG / NIA NIH HHS / United States
NS‐061836 / NS / NINDS NIH HHS / United States
5R01MH63706:02 / MH / NIMH NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
WT089062 / WT_ / Wellcome Trust / United Kingdom
AA17688 / AA / NIAAA NIH HHS / United States
R01-HL087641 / HL / NHLBI NIH HHS / United States
NS17950 / NS / NINDS NIH HHS / United States
G0500539 / MRC_ / Medical Research Council / United Kingdom
DA012854 / DA / NIDA NIH HHS / United States
R01D0042157‐01A / / PHS HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
AA15416 / AA / NIAAA NIH HHS / United States
MR/N01104X/1 / MRC_ / Medical Research Council / United Kingdom
R01 NS-42733 / NS / NINDS NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
CA‐47988 / CA / NCI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
WT089549 / WT_ / Wellcome Trust / United Kingdom
HL‐099355 / HL / NHLBI NIH HHS / United States
AA‐00145 / AA / NIAAA NIH HHS / United States
R01-HL093029 / HL / NHLBI NIH HHS / United States
1RL1MH083268‐01 / MH / NIMH NIH HHS / United States
5R01HL087679‐02 / HL / NHLBI NIH HHS / United States
HL93029 / HL / NHLBI NIH HHS / United States
AA11998 / AA / NIAAA NIH HHS / United States
WT084724MA / WT_ / Wellcome Trust / United Kingdom
Z01 AG-000954-06 / AG / NIA NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
U01NS069208-01 / NS / NINDS NIH HHS / United States
FS/14/55/30806 / BHF_ / British Heart Foundation / United Kingdom
OSRP2/1006 / DMT_ / The Dunhill Medical Trust / United Kingdom
0600331 / MRC_ / Medical Research Council / United Kingdom
068545/Z/02 / WT_ / Wellcome Trust / United Kingdom
P30 AG010129 / AG / NIA NIH HHS / United States
AA14041 / AA / NIAAA NIH HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
HL-093029 / HL / NHLBI NIH HHS / United States
AA07535 / AA / NIAAA NIH HHS / United States
AA‐09203 / AA / NIAAA NIH HHS / United States
076113/B/04/Z / WT_ / Wellcome Trust / United Kingdom
G0000934 / MRC_ / Medical Research Council / United Kingdom
P30DK072488 / DK / NIDDK NIH HHS / United States
085475/Z/08/z / WT_ / Wellcome Trust / United Kingdom
U01 DK062418 / DK / NIDDK NIH HHS / United States
HL‐043851 / HL / NHLBI NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
R01 NS-39987 / NS / NINDS NIH HHS / United States
G0600705 / MRC_ / Medical Research Council / United Kingdom
R01HL086694 / HL / NHLBI NIH HHS / United States
MH081802 / MH / NIMH NIH HHS / United States