Details der Publikation - Familial analysis reveals rare risk variants for migraine in regulatory regions

Familial analysis reveals rare risk variants for migraine in regulatory regions

Abstract The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci..

Medienart:	E-Artikel

Erscheinungsjahr:	2020
Erschienen:	2020

Enthalten in:	Zur Gesamtaufnahme - volume:21
Enthalten in:	Neurogenetics - 21(2020), 3 vom: 19. Feb., Seite 149-157

Sprache:	Englisch

Beteiligte Personen:	Techlo, Tanya Ramdal [VerfasserIn] Rasmussen, Andreas Høiberg [VerfasserIn] Møller, Peter L. [VerfasserIn] Bøttcher, Morten [VerfasserIn] Winther, Simon [VerfasserIn] Davidsson, Olafur B. [VerfasserIn] Olofsson, Isa A. [VerfasserIn] Chalmer, Mona Ameri [VerfasserIn] Kogelman, Lisette J. A. [VerfasserIn] Nyegaard, Mette [VerfasserIn] Olesen, Jes [VerfasserIn] Hansen, Thomas Folkmann [VerfasserIn]

Links:	Volltext [kostenfrei]

BKL:	42.13$jMolekularbiologie 44.48$jMedizinische Genetik 44.46$jKlinische Pathologie
Themen:	Family study Gene regulation Genetics Genome-wide Migraine Rare-variant association analysis

RVK:	RVK Klassifikation ELIB24 ELIB09

Anmerkungen:	© The Author(s) 2020

doi:	10.1007/s10048-020-00606-5

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	OLC2117952763

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520			\|a Abstract The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.
650		4	\|a Genetics
650		4	\|a Genome-wide
650		4	\|a Rare-variant association analysis
650		4	\|a Migraine
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650		4	\|a Family study
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700	1		\|a Nyegaard, Mette \|4 aut
700	1		\|a Olesen, Jes \|4 aut
700	1		\|a Hansen, Thomas Folkmann \|0 (orcid)0000-0001-6703-7762 \|4 aut
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773	1	8	\|g volume:21 \|g year:2020 \|g number:3 \|g day:19 \|g month:02 \|g pages:149-157
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Familial analysis reveals rare risk variants for migraine in regulatory regions

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