CHAPTER 10 220 10 descent) was published by Choqet et al.,116 reporting 95 single nucleotide polymorphisms (SNPs) to be associated with migraine. When putting Chapter 8 and this new GWAS next to each other 99 SNPs were unique to our study, 11 were unique to Choquet et al. and 68 were found in both studies. Choquet et al. also identified 3 loci specific for woman, this means that there are now in total at least 181 SNPs robustly associated with migraine.116 A benefit of finding as many risk loci as was done in migraine, is that these loci can be used to give biological meaning to the data, by detecting related genes or relevant functional groups, pathways and tissues with specific integrative analyses tools/software. There is a wide range of tools that can be used, all with their own specific goals and methodologies. Although pathway analysis have resulted in finding biomarkers for other diseases than migraine,117, 118 proper application and interpretation is not straightforward.119 In the cluster headache studies (Chapters 6 and 7) the number of loci was too few to perform these analysis. Apart from giving biological meaning to samples, there are also bioinformatics approaches that can be used to add clinical meaning to genetic data or to better understand the relationships with other traits. Again proper usage is important, as with all statistical analyses assumptions are made regarding the data, which need to be understood by the researcher. In addition, sufficient power needs to be present to perform the analyses, and therefore a large enough sample sizes is necessary. One of the methods uses polygenic risk scores (PRSs), which interrogates information of all the variants identified in GWAS and the combined effect of all these risk loci can be used to estimate a specific risk in a cohort. In breast cancer such a score is already being used for distinguishing women with a high and a low risk of breast cancer and advising sufficient preventative screening programs.120 Multiple studies have been performed with calculating a PRS in migraine and relating it to a specific trait. However, to what extend such a score is of benefit in the current clinical setting is hard to envisage, as in contrast to breast cancer migraine is a disease with attacks and prevention has a different meaning. A possibility would be in assessing whether somebody is likely to respond to certain medications, as medications are expensive and reaching the desired concentration of effect also takes time. One study has investigated the migraine PRS in relation to treatment response.121 However, there is still much to be improved on this study, indicating that a lot more work is to be done. Another methods to infer clinical meaning is Mendelian Randomisation (MR) with MR analysis one can investigate causality between two traits with genetic data via a statistical method. In the last 5 years this has already resulted in over 20 MR studies investigating causal relationships with migraine for various traits. These studies focussed on traits that had already shown an association with migraine in epidemiological studies. Important traits that were investigated are again the cardiovascular and cerebrovascular diseases, given they are well known comorbidities of migraine.2-5 The causal relationship of migraine with related traits such as stroke, blood pressure and coronary artery disease and migraine were investigated. Causality with migraine and stroke was examined based on GWAS data in three different studies by three different groups. Two studies, did not find a
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