title: Genetics of migraine in the age of genome-wide association studies.
abstract: Genetic factors importantly contribute to migraine. However, unlike for rare monogenic forms of migraine, approaches to identify genes for common forms of migraine have been of limited success. Candidate gene association studies were often negative and positive results were often not replicated or replication failed. Further, the significance of positive results from linkage studies remains unclear owing to the inability to pinpoint the genes under the peaks that may be involved in migraine. Problems hampering these studies include limited sample sizes, methods of migraine ascertainment, and the heterogeneous clinical phenotype. Three genome-wide association studies are available now and have successfully identified four new genetic variants associated with migraine. One new variant (rs1835740) modulates glutamate homeostasis, thus integrates well with current concepts of neurotransmitter disturbances. This variant may be more specific for severe forms of migraine such as migraine with aura than migraine without aura. Another variant (rs11172113) implicates the lipoprotein receptor LRP1, which may interact with neuronal glutamate receptors, thus also providing a link to the glutamate pathway. In contrast, rs10166942 is in close proximity to TRPM8, which codes for a cold and pain sensor. For the first time this links a gene explicitly implicated in pain related pathways to migraine. The potential function of the fourth variant rs2651899 (PRDM16) in migraine is unclear. All these variants only confer a small to moderate change in risk for migraine, which concurs with migraine being a heterogeneous disorder. Ongoing large international collaborations will likely identify additional gene variants for migraine.
authors.affiliation: Department of Neurology, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany. markus.schuerks@uni-due.de
authors.forename: Markus
authors.initials: M
authors.lastname: Schürks
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics*; D008881:Migraine Disorders / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050053:TRPM Cation Channels / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C416371:PRDM16 protein, human; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D014157:Transcription Factors
references.citation: Genes Dev. 2009 Apr 1;23(7):788-97
references.pmid: 19339685
references.citation: Cephalalgia. 2007 Aug;27(8):981-7
references.pmid: 17661875
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4687-92
references.pmid: 11287655
references.citation: Am J Hum Genet. 2003 Nov;73(5):986-93
references.pmid: 14513409
references.citation: Cephalalgia. 2007 Nov;27(11):1293-300
references.pmid: 17970989
references.citation: Am J Hum Genet. 2005 Sep;77(3):500-12
references.pmid: 16080125
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2542-6
references.pmid: 7681602
references.citation: Am J Hum Genet. 2006 Jul;79(1):85-99
references.pmid: 16773568
references.citation: Neurogenetics. 2002 Mar;4(1):17-22
references.pmid: 12030327
references.citation: Curr Pain Headache Rep. 2006 Jun;10(3):167-78
references.pmid: 18778570
references.citation: Neurology. 2007 May 8;68(19):1563-70
references.pmid: 17460157
references.citation: Cell. 2002 Mar 8;108(5):705-15
references.pmid: 11893340
references.citation: Acta Neurol (Napoli). 1991 Apr;13(2):205-11
references.pmid: 1891987
references.citation: Nat Genet. 2003 Feb;33(2):192-6
references.pmid: 12539047
references.citation: Headache. 2003 Mar;43(3):235-44
references.pmid: 12603642
references.citation: Science. 1996 Nov 29;274(5292):1527-31
references.pmid: 8929413
references.citation: Lancet Neurol. 2007 Jun;6(6):521-32
references.pmid: 17509487
references.citation: Headache. 2001 Feb;41(2):129-37
references.pmid: 11251696
references.citation: Hum Genet. 2009 Jul;126(1):115-32
references.pmid: 19455354
references.citation: Nat Genet. 2010 Oct;42(10):869-73
references.pmid: 20802479
references.citation: Lancet Neurol. 2006 Feb;5(2):148-157
references.pmid: 16426991
references.citation: Am J Hum Genet. 2003 Jan;72(1):161-7
references.pmid: 12474141
references.citation: Headache. 2002 May;42(5):352-5
references.pmid: 12047335
references.citation: Cephalalgia. 2010 Nov;30(11):1306-28
references.pmid: 20959426
references.citation: Headache. 1977 Jul;17(3):129-31
references.pmid: 893082
references.citation: Am J Med. 2005 Mar;118 Suppl 1:3S-10S
references.pmid: 15841882
references.citation: Expert Opin Investig Drugs. 2009 Jun;18(6):789-803
references.pmid: 19426123
references.citation: J Neural Transm Gen Sect. 1995;102(3):247-54
references.pmid: 8788073
references.citation: Twin Res Hum Genet. 2006 Feb;9(1):54-63
references.pmid: 16611468
references.citation: Headache. 2010 Apr;50(4):588-99
references.pmid: 19925624
references.citation: Mol Genet Genomics. 2011 Jun;285(6):433-46
references.pmid: 21519858
references.citation: Nat Rev Neurosci. 2003 May;4(5):386-98
references.pmid: 12728266
references.citation: Headache. 2006 Jun;46 Suppl 1:S3-8
references.pmid: 16927957
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3195-9
references.pmid: 9096369
references.citation: Scand J Immunol. 1996 Apr;43(4):456-63
references.pmid: 8668926
references.citation: Lancet. 2005 Jul 30-Aug 5;366(9483):371-7
references.pmid: 16054936
references.citation: Cephalalgia. 2011 Oct;31(13):1381-404
references.pmid: 22001640
references.citation: Expert Rev Neurother. 2008 May;8(5):781-97
references.pmid: 18457535
references.citation: Br J Haematol. 1995 Oct;91(2):490-501
references.pmid: 8547101
references.citation: Am J Hum Genet. 2008 May;82(5):1051-63
references.pmid: 18423523
references.citation: Eur J Hum Genet. 2011 Aug;19(8):901-7
references.pmid: 21448238
references.citation: Cephalalgia. 2007 Nov;27(11):1308-14
references.pmid: 17970991
references.citation: Cell. 1996 Nov 1;87(3):543-52
references.pmid: 8898206
references.citation: J Neurochem. 1996 Jun;66(6):2621-4
references.pmid: 8632190
references.citation: Am J Hum Genet. 2005 Feb;76(2):327-33
references.pmid: 15586324
references.citation: Hum Mol Genet. 2008 Nov 1;17(21):3318-31
references.pmid: 18676988
references.citation: Headache. 2005 Jul-Aug;45(7):926-31
references.pmid: 15985111
references.citation: JAMA. 2006 Apr 19;295(15):1824-30
references.pmid: 16622144
references.citation: Curr Biol. 2006 Aug 22;16(16):1591-605
references.pmid: 16920620
references.citation: Hum Mol Genet. 2003 Oct 1;12(19):2511-7
references.pmid: 12915447
references.citation: Lancet. 2004 Jan 31;363(9406):381-91
references.pmid: 15070571
references.citation: Br J Anaesth. 2008 Jul;101(1):48-58
references.pmid: 18511441
references.citation: Neurology. 1998 May;50(5):1428-32
references.pmid: 9596000
references.citation: Am J Hum Genet. 2002 Mar;70(3):652-62
references.pmid: 11836652
references.citation: Curr Opin Neurol. 2004 Jun;17(3):289-93
references.pmid: 15167063
references.citation: Physiol Rev. 2008 Jul;88(3):887-918
references.pmid: 18626063
references.citation: Cephalalgia. 2010 Nov;30(11):1296-305
references.pmid: 20959425
references.citation: Acta Neurol (Napoli). 1990 Aug;12(4):257-63
references.pmid: 2251950
references.citation: Genet Epidemiol. 2004 Apr;26(3):231-44
references.pmid: 15022209
references.citation: Cephalalgia. 2006 Mar;26(3):225-32
references.pmid: 16472327
references.citation: Neurology. 2002 Dec 10;59(11):1804-7
references.pmid: 12473779
references.citation: Neurology. 2007 Jun 5;68(23):1995-2002
references.pmid: 17460155
references.citation: BMJ. 2009 Oct 27;339:b3914
references.pmid: 19861375
references.citation: Nat Genet. 2011 Jun 12;43(7):695-8
references.pmid: 21666692
references.citation: Cephalalgia. 2004;24 Suppl 1:9-160
references.pmid: 14979299
references.citation: Ann Neurol. 2009 May;65(5):491-8
references.pmid: 19479724
references.citation: Headache. 2007 Apr;47 Suppl 1:S58-63
references.pmid: 17425711
references.citation: Twin Res. 2003 Oct;6(5):422-31
references.pmid: 14624726
references.citation: Cephalalgia. 1997 Jun;17(4):488-91; discussion 487
references.pmid: 9209767