Genetic Basis of Migraine

Heredity plays a prominent role in most cases of migraine. In clinical practice, it is commonplace to find that individuals with migraine have first-degree relatives with a history of the disorder.[1] The link between incidence of migraine in parent and child was first recognized in the 17th century and results from numerous genetic studies have substantiated this observation.[2, 3]

Genetic epidemiology

Results from twin studies and population-based surveys have demonstrated the important role that genetics plays in migraine. Ulrich and colleagues used a populationa-based sample from the New Danish Twin Register to examine the influence of genetics in causing migraine.[4] The study found significantly higher pairwise concordance rates in monozygotic versus dizygotic twin pairs (34% versus 12%, respectively; P=0.0003), a finding that indicates the importance of genetic factors migraine. Results from population-based surveys using segregation analysis to examine the mode of inheritance in migraine with and without aura indicate that genetic factors play an important role in both types of migraine, with inheritance likely multifactorial in nature and environmental factors also playing a role in phenotypic expression.[5, 6]

Familial Hemiplegic Migraine

Familial hemiplegic migraine (FHM), an uncommon form of migraine that is autosomal dominantly inherited, was the first subtype of migraine to be associated with specific genetic mutations.[7] Three distinct genetic abnormalities, including a mutations at CACNA1A on chromosome 19p13, ATP1A2 on chromosome 1q23, and on chromosome 2q24, have been associated with FHM.[1, 7] The mutation at CACNA1A on chromosome 19p13 encodes a subunit of P/Q-type calcium channel specific to brain and is associated with FHM Type 1. It accounts for about 50% of FHM families. The mutation at ATP1A2 on chromosome 1q23 encodes a subunit of Na+/K+ pump and is associated with FHM Type 2. It accounts for about 20% of FHM families. The mutation on chromosome 2q24, associated with FHM type 3, results in smaller electrochemical gradient for Na+.[7]

Linkage analysis and association studies

Results from linkage analysis and genetic association studies suggest that the genetic basis of migraine is likely complex and heterogeneic, involving an additive effect of multiple genes.[7] Abnormalities linked to migraine include genes encoding membrane channels, receptor families, and enzyme systems (Table 1). A variety of polymorphisms have been implicated in more common forms of migraine, such as migraine with and without aura.

Table 1. Genetic Sites Proposed to Be Important in the Common Forms of Migraine
Chromosome/Locus Gene/Protein Migraine Type
1p13.3 Glutathione S-Transferase (GST) MO
1 p36 MTHF-R MA
4 q24 Unknown MA & MO
4 q21
4q31.2 Endothelin type A (ETA-231 A/G) Not specified
6 p12—21 Unknown MA & MO
6p21.3 Tumor necrosis factor a (TNFa) Not specified
6p21.3 HLA-DRB1 MO
6q25.1 Estrogen receptor 1 (ESR1) MA & MO
6q25.1 Estrogen receptor 1 (ESR1) Not specified Females only
9q34 Dopamine b-hydroxylase (DBH) Not specified
11 q24 Unknown MA
11 p15 DRD4 MO
11q22—23 Progesterone receptor (PGR) MA & MO
11q23 DRD2 Allele 1 TG dinucleotide non-coding MO
11q23 Dopamine D2 (DRD2) NcoI MA
14 q21—22 Unknown MO
17q11.1-q12 Human serotonin transporter (SLC6A4) MA & MO
17q23 Angiotensin converting enzyme (ACE) MO
19p13.3/2 Insulin receptor INSR Not specified
22q11.2 Catechol-O-methyltransferase (COMT) not specified
X q24—28 Unknown MO
MA, migraine with aura; MO, migraine without aura.

Based on Cutrer FM. Semin Neurol. 2010;30:120-30.

Written by: Jonathan Simmons, PhD | Last review date: March 2012.
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