Functional insights into the pathology of migraine subtypes, with and without aura

Bjornsdottir G, Chalmer MA, Stefansdottir L, Skuladottir AT, Einarsson G, Andresdottir M, Beyter D, Ferkingstad E, Gretarsdottir S, Halldorsson BV, Halldorsson GH, Helgadottir A, Helgason H, Hjorleifsson Eldjarn G, Jonasdottir A, Jonasdottir A, Jonsdottir I, Knowlton KU, Nadauld LD, Lund SH, Magnusson OT, Melsted P, Moore KHS, Oddsson A, Olason PI, Sigurdsson A, Stefansson OA, Saemundsdottir J, Sveinbjornsson G, Tragante V, Unnsteinsdottir U, Walters GB, Zink F, Rødevand L, Andreassen OA, Igland J, Lie RT, Haavik J, Banasik K, Brunak S, Didriksen M, T Bruun M, Erikstrup C, Kogelman LJA, Nielsen KR, Sørensen E, Pedersen OB, Ullum H; DBDS Genetic Consortium; Masson G, Thorsteinsdottir U, Olesen J, Ludvigsson P, Thorarensen O, Bjornsdottir A, Sigurdardottir GR, Sveinsson OA, Ostrowski SR, Holm H, Gudbjartsson DF, Thorleifsson G, Sulem P, Stefansson H, Thorgeirsson TE, Hansen TF, Stefansson K. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura. Nat Genet. 2023 Nov;55(11):1843-1853. doi: 10.1038/s41588-023-01538-0. Epub 2023 Oct 26. PMID: 37884687; PMCID: PMC10632135.
Abstract


Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

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An analysis of genetic data from more than 1.3 million people has revealed new biological pathways associated with migraine that could potentially be targeted for drug development. Researchers published their findings in Nature Genetics.

“Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes,” wrote corresponding author Gyda Bjornsdottir, PhD, of deCODE Genetics, a subsidiary of Amgen Inc. based in Reykjavik, Iceland, and study coauthors.

The analysis combined large genome-wide association study (GWAS) datasets from 6 European populations in an attempt to detect sequence variants associated with the two main subtypes of migraine: migraine with aura and migraine without aura. Among participants sequenced, 17,000 had migraine with aura, 12,000 had migraine without aura, and 80,000 had any migraine.

Migraine was associated with 44 variants, according to the study. Twelve of the associations were novel, while 4 new associations were identified for migraine with aura (in PRRT2, PALMD, ABO, and LRRK2), and 13 variants were classified for migraine without aura.

The research team reported rare variants with large effects highlighting 3 genes. First, a rare frameshift variant in the PRRT2 gene conferred a large risk of migraine with aura and epilepsy, but not migraine without aura. Second, a burden test of rare loss-of-function variants in the SCN11A gene, which plays a key role in pain sensation, showed strong protection against migraine. Meanwhile, a common missense variant in SCN11A was associated with modest migraine risk.

Third, a rare variant pointing to the KCNK5 gene conferred large protection against migraine and brain aneurysms. The finding either identifies a common pathway between the two diseases or suggests that some cases of undetected brain aneurysms may be misclassified as migraine, the team explained.

“In all, our findings are consistent with the results of previous GWAS analyses that have established migraine as a complex neurovascular brain disorder,” researchers wrote. “However, our results also highlight several distinct biological pathways involved in migraine with aura and migraine without aura that warrant further study.”

https://www.hmpgloballearningnetwork.com/site/neuro/news/novel-migraine-pathways-could-guide-drug-development