Dataset Information

Common variants at 5q33.1 predispose to migraine in African-American children.

ABSTRACT:

Background

Genome-wide association studies (GWASs) have identified multiple susceptibility loci for migraine in European adults. However, no large-scale genetic studies have been performed in children or African Americans with migraine.

Methods

We conducted a GWAS of 380 African-American children and 2129 ancestry-matched controls to identify variants associated with migraine. We then attempted to replicate our primary analysis in an independent cohort of 233 African-American patients and 4038 non-migraine control subjects.

Results

The results of this study indicate that common variants at 5q33.1 associated with migraine risk in African-American children (rs72793414, p=1.94×10^-9). The association was validated in an independent study (p=3.87×10^-3) for an overall meta-analysis p value of 3.81×10^-10. eQTL (Expression quantitative trait loci) analysis of the Genotype-Tissue Expression data also shows the genotypes of rs72793414 were strongly correlated with the mRNA expression levels of NMUR2 at 5q33.1. NMUR2 encodes a G protein-coupled receptor of neuromedin-U (NMU). NMU, a highly conserved neuropeptide, participates in diverse physiological processes of the central nervous system.

Conclusions

This study provides new insights into the genetic basis of childhood migraine and allow for precision therapeutic development strategies targeting migraine patients of African-American ancestry.

SUBMITTER: Chang X

PROVIDER: S-EPMC6511513 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Common variants at 5q33.1 predispose to migraine in African-American children.

Chang Xiao X Pellegrino Renata R Garifallou James J March Michael M Snyder James J Mentch Frank F Li Jin J Hou Cuiping C Liu Yichuan Y Sleiman Patrick M A PMA Hakonarson Hakon H

Journal of medical genetics 20180928 12

<h4>Background</h4>Genome-wide association studies (GWASs) have identified multiple susceptibility loci for migraine in European adults. However, no large-scale genetic studies have been performed in children or African Americans with migraine.<h4>Methods</h4>We conducted a GWAS of 380 African-American children and 2129 ancestry-matched controls to identify variants associated with migraine. We then attempted to replicate our primary analysis in an independent cohort of 233 African-American pati ...[more]

PMID: 30266756

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Project description:BackgroundMultiple reports associate the cardiac sodium channel gene (SCN5A) variants S1103Y and R1193Q with type 3 congenital long QT syndrome and drug-induced long QT syndrome. These variants are too common in ancestral populations to be highly arrhythmogenic at baseline, however: S1103Y allele frequency is 8.1% in African Americans and R1193Q 6.1% in East Asians. R1193Q is known to increase late sodium current (INa-L) in cardiomyocytes derived from induced pluripotent stem cells but the role of these variants in modulating repolarization remains poorly understood.MethodsWe determined the effect of S1103Y on QT intervals among African-American participants in a large electronic health record. Using cardiomyocytes derived from induced pluripotent stem cells carrying naturally occurring or genome-edited variants, we studied action potential durations (APDs) at baseline and after challenge with the repolarizing potassium current (IKr) blocker dofetilide and INa-L and IKr at baseline.ResultsIn 1479 African-American participants with no confounding medications or diagnoses of heart disease, QT intervals in S1103Y carriers was no different from that in noncarriers. Baseline APD was no different in cells expressing the Y allele (SY, YY cells) compared with isogenic cells with the reference allele (SS cells). However, INa-L was increased in SY and YY cells and the INa-L blocker GS967 shortened APD in SY/YY but not SS cells (P<0.001). IKr was increased almost 2-fold in SY/YY cells compared with SS cells (tail current: 0.66±0.1 versus 1.2±0.1 pA/pF; P<0.001). Dofetilide challenge prolonged APD at much lower concentrations in SY (4.1 nmol/L [interquartile range, 1.5-9.3]; n=11) and YY (4.2 nmol/L [1.7-5.0]; n=5) than in SS cells (249 nmol/L [22.3-2905]; n=14; P<0.001 and P<0.01, respectively) and elicited afterdepolarizations in 8/16 SY/YY cells but only in 1/14 SS cells. R1193Q cells similarly displayed no difference in baseline APD but increased IKr and increased dofetilide sensitivity.ConclusionsThese common ancestry-specific variants do not affect baseline repolarization, despite generating increased INa-L. We propose that increased IKr serves to maintain normal repolarization but increases the risk of manifest QT prolongation with IKr block in variant carriers. Our findings emphasize the need for inclusion of diverse populations in the study of adverse drug reactions.

Dataset Information

Common variants at 5q33.1 predispose to migraine in African-American children.

Background

Methods

Results

Conclusions

Publications

Common variants at 5q33.1 predispose to migraine in African-American children.

Similar Datasets

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