Family studies to find rare high risk variants in migraine

INTRODUCTION: Migraine has long been known as a common complex disease caused by genetic and environmental factors. The pathophysiology and the specific genetic susceptibility are poorly understood. Common variants only explain a small part of the heritability of migraine. It is thought that rare genetic variants with bigger effect size may be involved in the disease. Since migraine has a tendency to cluster in families, a family approach might be the way to find these variants. This is also indicated by identification of migraine-associated loci in classical linkage-analyses in migraine families. A single migraine study using a candidate-gene approach was performed in 2010 identifying a rare mutation in the TRESK potassium channel segregating in a large family with migraine with aura, but this finding has later become questioned. The technologies of next-generation sequencing (NGS) now provides an affordable tool to investigate the genetic variation in the entire exome or genome. The family-based study design using NGS is described in this paper. We also review family studies using NGS that have been successful in finding rare variants in other common complex diseases in order to argue the promising application of a family approach to migraine. METHOD: PubMed was searched to find studies that looked for rare genetic variants in common complex diseases through a family-based design using NGS, excluding studies looking for de-novo mutations, or using a candidate-gene approach and studies on cancer. All issues from Nature Genetics and PLOS genetics 2014, 2015 and 2016 (UTAI June) were screened for relevant papers. Reference lists from included and other relevant papers were also searched. For the description of the family-based study design using NGS an in-house protocol was used. RESULTS: Thirty-two successful studies, which covered 16 different common complex diseases, were included in this paper. We also found a single migraine study. Twenty-three studies found one or a few family specific variants (less than five), while other studies found several possible variants. Not all of them were genome wide significant. Four studies performed follow-up analyses in unrelated cases and controls and calculated odds ratios that supported an association between detected variants and risk of disease. Studies of 11 diseases identified rare variants that segregated fully or to a large degree with the disease in the pedigrees. CONCLUSION: It is possible to find rare high risk variants for common complex diseases through a family-based approach. One study using a family approach and NGS to find rare variants in migraine has already been published but with strong limitations. More studies are under way. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s10194-017-0729-y) contains supplementary material, which is available to authorized users

Migraine polygenic risk score associates with efficacy of migraine-specific drugs

Objective To assess whether the polygenic risk score (PRS) for migraine is associated with acute and/or prophylactic migraine treatment response. Methods We interviewed 2,219 unrelated patients at the Danish Headache Center using a semistructured interview to diagnose migraine and assess acute and prophylactic drug response. All patients were genotyped. A PRS was calculated with the linkage disequilibrium pred algorithm using summary statistics from the most recent migraine genome-wide association study comprising similar to 375,000 cases and controls. The PRS was scaled to a unit corresponding to a twofold increase in migraine risk, using 929 unrelated Danish controls as reference. The association of the PRS with treatment response was assessed by logistic regression, and the predictive power of the model by area under the curve using a case-control design with treatment response as outcome. Results A twofold increase in migraine risk associates with positive response to migraine-specific acute treatment (odds ratio [OR] = 1.25 [95% confidence interval (CI) = 1.05-1.49]). The association between migraine risk and migraine-specific acute treatment was replicated in an independent cohort consisting of 5,616 triptan users with prescription history (OR = 3.20 [95% CI = 1.26-8.14]). No association was found for acute treatment with non-migraine-specific weak analgesics and prophylactic treatment response. Conclusions The migraine PRS can significantly identify subgroups of patients with a higher-than-average likelihood of a positive response to triptans, which provides a first step toward genetics-based precision medicine in migraine.Peer reviewe

Genotype–phenotype correlation in migraine without aura focusing on the rs1835740 variant on 8q22.1

A large two-stage GWAS by Antilla et al. reported the minor allele of rs1835740 on 8q22.1 to be associated with common types of migraine. The objective of the present study was to determine the clinical correlate of the variant in migraine without aura (MO). Clinical data on 339 successfully genotyped MO patients (patients with attacks of migraine without aura and no attacks of migraine with aura) were obtained by an extensive validated semi-structured telephone interview performed by a physician or a trained senior medical student. Reliable, systematic and extensive data on symptoms, age of onset, attack frequencies and duration, relevant comorbidity, specific provoking factors including different hormonal factors in females, and effect and use of medication, both abortive and prophylactic, were thereby obtained. A comparison of carriers and non-carriers were performed. Comparison of homozygotes with heterozygotes was not performed as the number of homozygotes was too small for statistical purposes. Data from other MO populations in the GWAS by Antilla et al. were not included as phenotype and clinical data were obtained differently. While thousands of patients are needed to detect a genetic variant like rs1835740, 339 are sufficient to detect meaningful clinical differences. 136 of 339 patients were carriers of the variant, 15 were homozygous. Comparison of carriers with non-carriers showed no significant difference in any of the parameters studied. In conclusion, the rs1835740 variant has no significant influence on the clinical expression of MO

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Migraine polygenic risk score associates with efficacy of migraine-specific drugs

Objective To assess whether the polygenic risk score (PRS) for migraine is associated with acute and/or prophylactic migraine treatment response. Methods We interviewed 2,219 unrelated patients at the Danish Headache Center using a semistructured interview to diagnose migraine and assess acute and prophylactic drug response. All patients were genotyped. A PRS was calculated with the linkage disequilibrium pred algorithm using summary statistics from the most recent migraine genome-wide association study comprising ∼375,000 cases and controls. The PRS was scaled to a unit corresponding to a twofold increase in migraine risk, using 929 unrelated Danish controls as reference. The association of the PRS with treatment response was assessed by logistic regression, and the predictive power of the model by area under the curve using a case-control design with treatment response as outcome. Results A twofold increase in migraine risk associates with positive response to migraine-specific acute treatment (odds ratio [OR] = 1.25 [95% confidence interval (CI) = 1.05–1.49]). The association between migraine risk and migraine-specific acute treatment was replicated in an independent cohort consisting of 5,616 triptan users with prescription history (OR = 3.20 [95% CI = 1.26–8.14]). No association was found for acute treatment with non–migraine-specific weak analgesics and prophylactic treatment response. Conclusions The migraine PRS can significantly identify subgroups of patients with a higher-than-average likelihood of a positive response to triptans, which provides a first step toward genetics-based precision medicine in migraine

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies