CHAPTER 1 14 1 Rationale for genetic studies When identifying genes involved in a disorder, different approaches are used depending on the disorder’s architecture (i.e. monogenic, oligogenic or polygenic). The more oligogenic a disease is (i.e. the smaller the number of genes involved, with monogenic being the extreme), the larger the effect size of the associated gene variant(s) tends to be (Figure 2), in line with epidemiological data from disorders where rare disorders are monogenic and common disorders polygenic. Hemiplegic migraine Most of our knowledge of molecular mechanisms in migraine pathophysiology came from studying rare hemiplegic migraine (HM). The classical linkage method in migraine research was used to study large families with HM and this revealed a clear Mendelian (monogenic) type of inheritance. The approach led to the identification of three undisputed HM genes; CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3).87-89 Figure 2 Relationship between different types of hereditary (monogenic vs. polygenic) disorders. Illustrating the relation to the allele frequency and the corresponding effect size as well as the contribution of genetic variants vs. environmental factors. Adapted from Manolio et al.90 In many patients with HM no pathogenic mutation has been detected in the HM genes.91, 92 In recent years, whole-exome (next-generation) sequencing (WES) has been used to try and identify additional causal genes in patients without mutations in the known HM genes, but this has been proven difficult and no “fourth” gene has been identified thus far.93 A study by Pelzer et al.93 did,
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