Migraine Genetics
Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine (FHM). The first FHM gene that was identified is CACNA1A. A second gene, FHM2, has been mapped to chromosome 1 q 21–23. The defect is a new mutation in the α2 subunit of the Na/K pump (ATP1A2). A third gene (FHM3) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A (Gln1489Lys), which encodes an α1 subunit of a neuronal voltage-gated Na+ channel. Genome-wide association studies have identified many non-coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two-pore domain potassium channel, TWIK-related spinal cord potassium channel. TWIK-related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.
In the first of this 2-part series on migraine genetics, we reviewed the fundamentals of molecular genetics and the recent advances that are important for understanding the genetics of migraine. This companion paper provides an update on the genetic advances in migraine and insights into the pathogenesis that these advances have provided.
Migraine is recognized to cluster in families and has long been considered to be a strongly heritable disorder. Migraine, with (MWA) or without (MWoA) aura, has a substantial risk of familial occurrence, and genetic epidemiologic studies suggest that MWoA and MWA have distinct and unique heritability; first-degree relatives of MWoA probands have 1.9 times the risk of MWoA and 1.4 times the risk of MWA, whereas first-degree relatives of MWA probands have nearly 4 times the risk of MWA and no increased risk of MWoA. Concordance rates for migraine are higher among monozygotic (MZ) than dizygotic (DZ) twins; heritability estimates are around 52% in female twin pairs raised together or apart since infancy. In MZ Danish twin pairs, liability to MWoA resulted from additive genetic effects (61%) and from individual-specific environmental effects (39%), while in MWA, correlation in liability was 0.68 in MZ and 0.22 in DZ, with heritability estimated at 0.65. Twin studies reveal that approximately one half of the variation in migraine is attributable to additive genes, while the remainder is caused by unshared rather than shared environmental factors between twins.
Complex segregation analyses have demonstrated that a multifactorial heredity model, wherein multiple genetic susceptibility factors interact with multiple environmental factors and render an individual susceptible to recurrent attacks, is most compatible with the mode of inheritance of migraine. Migraine, like many complex multifactorial inherited diseases, is cotransmitted with other disorders. Migraine, anxiety, and depression are comorbid and share common genetic traits.
As reviewed in part 1 of this 2-part series, identifying genes for multifactorial disorders like migraine is challenging because multiple genes, most with low penetrance, contribute to susceptibility of the disorder. Moreover, the resulting phenotype is influenced by both endogenous and exogenous non-genetic factors. Case ascertainment can be a serious confounder that influences the validity of genetic analysis, particularly with migraine, in which there is no biomarker to aid in diagnosis. Thus, for large population-based studies, questionnaires, which are less reliable than the gold standard specialist interview, are relied upon not only for case ascertainment, but for control ascertainment as well.
Several strategies have been employed to identify genes for migraine. The most successful approach has been the identification of gene mutations in families with familial hemiplegic migraine (FHM), a rare monogenic subtype of migraine. This has been done using positional cloning techniques, mutation analysis, and traditional linkage analysis, which require testing several hundreds or thousands of genetic markers across the genome and selecting those chromosomal regions that most closely segregate with the disease. This strategy is based on the hypothesis that rare monogenic subtypes share common genes and gene product-related physiological mechanisms with more common types of migraine.
A second linkage analysis strategy that is often used in complex traits is affected sib-pair analysis, in which chromosomal regions shared by affected siblings that occur with a probability higher than by chance alone are identified. This is then followed by case–control association studies, testing single-nucleotide polymorphisms (SNPs) in candidate genes in the shared regions. The goal is to identify SNPs, and thus gene alleles, that statistically differ in frequency between cases and controls, and cause increased susceptibility to the disease. A third, hypothesis-driven approach is direct testing of candidate genes in case–control association studies. A promising extension of this approach is the possibility of testing for genome-wide association by scanning hundreds of thousands of SNPs in large and clinically homogenous populations. What follows is a discussion of the advances in the genetics of migraine utilizing each of these approaches.
Abstract and Introduction
Abstract
Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine (FHM). The first FHM gene that was identified is CACNA1A. A second gene, FHM2, has been mapped to chromosome 1 q 21–23. The defect is a new mutation in the α2 subunit of the Na/K pump (ATP1A2). A third gene (FHM3) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A (Gln1489Lys), which encodes an α1 subunit of a neuronal voltage-gated Na+ channel. Genome-wide association studies have identified many non-coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two-pore domain potassium channel, TWIK-related spinal cord potassium channel. TWIK-related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.
Introduction
In the first of this 2-part series on migraine genetics, we reviewed the fundamentals of molecular genetics and the recent advances that are important for understanding the genetics of migraine. This companion paper provides an update on the genetic advances in migraine and insights into the pathogenesis that these advances have provided.
Migraine is recognized to cluster in families and has long been considered to be a strongly heritable disorder. Migraine, with (MWA) or without (MWoA) aura, has a substantial risk of familial occurrence, and genetic epidemiologic studies suggest that MWoA and MWA have distinct and unique heritability; first-degree relatives of MWoA probands have 1.9 times the risk of MWoA and 1.4 times the risk of MWA, whereas first-degree relatives of MWA probands have nearly 4 times the risk of MWA and no increased risk of MWoA. Concordance rates for migraine are higher among monozygotic (MZ) than dizygotic (DZ) twins; heritability estimates are around 52% in female twin pairs raised together or apart since infancy. In MZ Danish twin pairs, liability to MWoA resulted from additive genetic effects (61%) and from individual-specific environmental effects (39%), while in MWA, correlation in liability was 0.68 in MZ and 0.22 in DZ, with heritability estimated at 0.65. Twin studies reveal that approximately one half of the variation in migraine is attributable to additive genes, while the remainder is caused by unshared rather than shared environmental factors between twins.
Complex segregation analyses have demonstrated that a multifactorial heredity model, wherein multiple genetic susceptibility factors interact with multiple environmental factors and render an individual susceptible to recurrent attacks, is most compatible with the mode of inheritance of migraine. Migraine, like many complex multifactorial inherited diseases, is cotransmitted with other disorders. Migraine, anxiety, and depression are comorbid and share common genetic traits.
As reviewed in part 1 of this 2-part series, identifying genes for multifactorial disorders like migraine is challenging because multiple genes, most with low penetrance, contribute to susceptibility of the disorder. Moreover, the resulting phenotype is influenced by both endogenous and exogenous non-genetic factors. Case ascertainment can be a serious confounder that influences the validity of genetic analysis, particularly with migraine, in which there is no biomarker to aid in diagnosis. Thus, for large population-based studies, questionnaires, which are less reliable than the gold standard specialist interview, are relied upon not only for case ascertainment, but for control ascertainment as well.
Several strategies have been employed to identify genes for migraine. The most successful approach has been the identification of gene mutations in families with familial hemiplegic migraine (FHM), a rare monogenic subtype of migraine. This has been done using positional cloning techniques, mutation analysis, and traditional linkage analysis, which require testing several hundreds or thousands of genetic markers across the genome and selecting those chromosomal regions that most closely segregate with the disease. This strategy is based on the hypothesis that rare monogenic subtypes share common genes and gene product-related physiological mechanisms with more common types of migraine.
A second linkage analysis strategy that is often used in complex traits is affected sib-pair analysis, in which chromosomal regions shared by affected siblings that occur with a probability higher than by chance alone are identified. This is then followed by case–control association studies, testing single-nucleotide polymorphisms (SNPs) in candidate genes in the shared regions. The goal is to identify SNPs, and thus gene alleles, that statistically differ in frequency between cases and controls, and cause increased susceptibility to the disease. A third, hypothesis-driven approach is direct testing of candidate genes in case–control association studies. A promising extension of this approach is the possibility of testing for genome-wide association by scanning hundreds of thousands of SNPs in large and clinically homogenous populations. What follows is a discussion of the advances in the genetics of migraine utilizing each of these approaches.
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