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A replication study of GWAS findings in migraine identifies association in a Swedish case-control sample.

ABSTRACT: Migraine is a common neurovascular disorder with symptoms including headache of moderate to severe intensity and recurring attacks. There is no cure for migraine today and the pathology is poorly understood. Common forms of migraine have a complex genetic background and heritability has been estimated to be around 50%. Recent genome-wide association studies (GWAS) on European and American migraine cohorts have led to the identification of new genetic risk factors for migraine.We performed an association study in a Swedish population based cohort, investigating the frequency of eight single nucleotide polymorphisms (SNPs) recently identified as genetic risk factors for migraine in three GWAS, using available array data (Illumina Omni Express chip). The eight SNPs were rs2651899, rs3790455, rs10166942, rs7640543, rs9349379, rs1835740, rs6478241 and rs11172113. Because information on rs3790455, rs10166942 and rs7640543 was not directly available, we selected SNPs in high Linkage Disequilibrium (LD) with these three SNPs, and replaced them with rs2274316, rs1003540 and rs4075749, respectively.We were able to replicate the association with rs2651899 and found a trend for association with rs1835740 in our Swedish cohort.This is the first reported genetic association study of a Swedish migraine case control material. We have thus replicated findings of susceptibility loci for migraine in an independent genetic material, thereby increasing knowledge about genetic risk factors for this common neurological disorder.

SUBMITTER: Ran C

PROVIDER: S-EPMC3986694 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A replication study of GWAS findings in migraine identifies association in a Swedish case-control sample.

Ran Caroline C Graae Lisette L Magnusson Patrik K E PK Pedersen Nancy L NL Olson Lars L Belin Andrea C AC

BMC medical genetics 20140328

<h4>Background</h4>Migraine is a common neurovascular disorder with symptoms including headache of moderate to severe intensity and recurring attacks. There is no cure for migraine today and the pathology is poorly understood. Common forms of migraine have a complex genetic background and heritability has been estimated to be around 50%. Recent genome-wide association studies (GWAS) on European and American migraine cohorts have led to the identification of new genetic risk factors for migraine. ...[more]

PMID: 24674449

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Project description:In the past decade, many genome-wide association studies (GWASs) have been conducted to explore association of single nucleotide polymorphisms (SNPs) with complex diseases using a case-control design. These GWASs not only collect information on the disease status (primary phenotype, D) and the SNPs (genotypes, X), but also collect extensive data on several risk factors and traits. Recent literature and grant proposals point toward a trend in reusing existing large case-control data for exploring genetic associations of some additional traits (secondary phenotypes, Y) collected during the study. These secondary phenotypes may be correlated, and a proper analysis warrants a multivariate approach. Commonly used multivariate methods are not equipped to properly account for the non-random sampling scheme. Current ad hoc practices include analyses without any adjustment, and analyses with D adjusted as a covariate. Our theoretical and empirical studies suggest that the type I error for testing genetic association of secondary traits can be substantial when X as well as Y are associated with D, even when there is no association between X and Y in the underlying (target) population. Whether using D as a covariate helps maintain type I error depends heavily on the disease mechanism and the underlying causal structure (which is often unknown). To avoid grossly incorrect inference, we have proposed proportional odds model adjusted for propensity score (POM-PS). It uses a proportional odds logistic regression of X on Y and adjusts estimated conditional probability of being diseased as a covariate. We demonstrate the validity and advantage of POM-PS, and compare to some existing methods in extensive simulation experiments mimicking plausible scenarios of dependency among Y, X, and D. Finally, we use POM-PS to jointly analyze four adiposity traits using a type 2 diabetes (T2D) case-control sample from the population-based Metabolic Syndrome in Men (METSIM) study. Only POM-PS analysis of the T2D case-control sample seems to provide valid association signals.

Project description:Infantile regurgitation is one of the most common discomforts in the first months of life. Infantile colic and, in older children, functional dyspepsia have been linked to migraine. To date, this is the first study to investigate a possible association between infantile regurgitation and primary headaches in children. This is a case-control study of 195 children aged 6-17 years, with primary headache (migraine, or tension type headache) in 5 European paediatric hospitals. The control group is composed of 240 same-aged children attending with minor injuries during the same period - February 1st 2020 to December 1st 2020. A structured questionnaire identified a history of infantile regurgitation and other functional gastrointestinal disorders for case and control participants. The outcome was the difference in the prevalence of infantile regurgitation among children with or without a diagnosis of primary headache. The analysis showed a significant association between infantile regurgitation and migraine (OR = 1.88, CI 95 = 1.01-3.4, p = 0.04). No association was found between infantile regurgitation and tension type headache (p = 0.33). Subgroup analysis confirmed that the association was only significant for migraine without aura (OR = 2.3, CI 95 = 1.2-4.4, p = 0.01). In a further subgroup analysis, the presence of functional dyspepsia, irritable bowel syndrome and abdominal migraine was associated with migraine without aura.ConclusionThe presence of migraine among children aged 6-17 was associated with a history of infantile regurgitation. Additional longitudinal studies are required to confirm whether infantile regurgitation could be considered as a precursor of migraine.What is known• Children suffering from functional gastrointestinal disorders are more likely to be suffering from migraine and tension-type headache as well. • Children suffering from primary headache are more likely to have had infantile colic in their first six month of life.What is new• It is the first study to find an association between migraine and infantile regurgitation in children. • These findings could have an impact on the diagnosis and therapeutics of both migraine and infantile regurgitation.

Project description:Genome-wide association studies (GWAS) explore the relationship between genome variability and disease susceptibility with either population- or family-based data. Here, we have evaluated the utility of combining population- and family-based statistical association tests and have proposed a method for reducing the burden of multiple testing. Unrelated singleton and parent-offspring trio cases and controls from the Genetics of Kidneys in Diabetes (GoKinD) study were analyzed for genetic association with diabetic nephropathy (DN) in type 1 diabetics (T1D). The Cochran-Armitage test for trend and the family-based association test were employed using either unrelated cases and controls or trios, respectively. In addition to combining single nucleotide polymorphism (SNP) p-values across these tests via Fisher's method, we employed a novel screening approach to rank SNPs based on conditional power for more efficient testing. Using either the population-based or family-based subset alone predictably limited resolution to detect DN SNPs. For 384,197 SNPs passing quality control (QC), none achieved strict genome-wide significance (1.4 × 10(-7)) using 1171 singletons (577/594 cases/controls) or 1738 pooled singletons and offspring probands (841/897). Similarly, none of the 352,004 SNPs passing QC in 567 family trios (264/303 case/control proband trios) reached genome-wide significance. Testing the top 10 SNPs ranked using aggregated conditional power resulted in two SNPs reaching genome-wide significance, rs11645147 on chromosome 16 (p = 1.74 × 10(-4) < 0.05/10 = 0.005) and rs7866522 on chromosome 9 (p = 0.0033). Efficient usage of mixed designs incorporating both unrelated and family-based data may help to uncover associations otherwise difficult to detect in the presence of massive multiple testing corrections. Capitalizing on the strengths of both types while using screening approaches may be useful especially in light of large-scale, next-generation sequencing and rare variant studies.

Dataset Information

A replication study of GWAS findings in migraine identifies association in a Swedish case-control sample.

Publications

A replication study of GWAS findings in migraine identifies association in a Swedish case-control sample.

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