Migraine: a complex genetic disorder

2004, The International Classification of Headache Disorders, 2nd edn, Cephalalgia, 24, 1 Pietrobon, 2003, Neurobiology of migraine, Nat Rev Neurosci, 4, 386, 10.1038/nrn1102 Stovner, 2006, Epidemiology of headache in Europe, Eur J Neurol, 13, 333, 10.1111/j.1468-1331.2006.01184.x Launer, 1999, The prevalence and characteristics of migraine in a population-based cohort: the GEM study, Neurology, 53, 537, 10.1212/WNL.53.3.537 Kruit, 2004, Migraine as a risk factor for subclinical brain lesions, JAMA, 291, 427, 10.1001/jama.291.4.427 Lipton, 2007, Migraine prevalence, disease burden, and the need for preventive therapy, Neurology, 68, 343, 10.1212/01.wnl.0000252808.97649.21 Goadsby, 2002, Migraine—current understanding and treatment, N Engl J Med, 346, 257, 10.1056/NEJMra010917 Menken, 2000, The global burden of disease study: implications for neurology, Arch Neurol, 57, 418, 10.1001/archneur.57.3.418 Andlin-Sobocki, 2005, Cost of disorders of the brain in Europe, Eur J Neurol, 12, 1, 10.1111/j.1468-1331.2005.01202.x Blau, 1992, Migraine: theories of pathogenesis, Lancet, 339, 1202, 10.1016/0140-6736(92)91140-4 Blau, 1995, Migraine with aura and migraine without aura are not different entities, Cephalalgia, 15, 186, 10.1046/j.1468-2982.1995.015003186.x Kallela, 2001, Familial migraine with and without aura: clinical characteristics and co-occurrence, Eur J Neurol, 8, 441, 10.1046/j.1468-1331.2001.00260.x Nyholt, 2004, Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities, Genet Epidemiol, 26, 231, 10.1002/gepi.10311 Russell, 2002, Migraine without aura and migraine with aura are distinct disorders: a population-based twin survey, Headache, 42, 332, 10.1046/j.1526-4610.2002.02102.x Guidetti, 2006, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Clin Exp Hypertens, 28, 271, 10.1080/10641960600549223 Bigal, 2003, Epilepsy and migraine, Epilepsy Behav, 4, S13, 10.1016/j.yebeh.2003.07.003 Lipton, 1994, Why study the comorbidity of migraine?, Neurology, 44, S4 Ludvigsson, 2006, Migraine with aura is a risk factor for unprovoked seizures in children, Ann Neurol, 59, 210, 10.1002/ana.20745 Breslau, 2003, Comorbidity of migraine and depression: investigating potential etiology and prognosis, Neurology, 60, 1308, 10.1212/01.WNL.0000058907.41080.54 Russell, 1995, Increased familial risk and evidence of genetic factor in migraine, BMJ, 311, 541, 10.1136/bmj.311.7004.541 Russell, 1995, Inheritance of migraine investigated by complex segregation analysis, Hum Genet, 96, 726, 10.1007/BF00210307 Honkasalo, 1995, Migraine and concomitant symptoms among 8167 adult twin pairs, Headache, 35, 70, 10.1111/j.1526-4610.1995.hed3502070.x Larsson, 1995, Genetic influence in headaches: a Swedish twin study, Headache, 35, 513, 10.1111/j.1526-4610.1995.hed3509513.x Gervil, 1999, Genetic and environmental factors in migraine, Neurology, 53, 995, 10.1212/WNL.53.5.995 Ulrich, 1999, Evidence of a genetic factor in migraine with aura: a population-based Danish twin study, Ann Neurol, 45, 242, 10.1002/1531-8249(199902)45:2<242::AID-ANA15>3.0.CO;2-1 Mulder, 2003, Genetic and environmental influences on migraine: a twin study across six countries, Twin Res, 6, 422, 10.1375/136905203770326420 Ziegler, 1998, Migraine in twins raised together and apart, Headache, 38, 417, 10.1046/j.1526-4610.1998.3806417.x Svensson, 2003, Shared rearing environment in migraine: results from twins reared apart and twins reared together, Headache, 43, 235, 10.1046/j.1526-4610.2003.03047.x Kors, 2001, Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine, Ann Neurol, 49, 753, 10.1002/ana.1031 Thomsen, 2003, Sporadic hemiplegic migraine is an aetiologically heterogeneous disorder, Cephalalgia, 23, 921, 10.1046/j.1468-2982.2003.00614.x Thomsen, 2004, Sporadic hemiplegic migraine, Cephalalgia, 24, 1016, 10.1111/j.1468-2982.2004.00788.x Thomsen, 2003, Evidence for a separate type of migraine with aura: Sporadic hemiplegic migraine, Neurology, 60, 595, 10.1212/01.WNL.0000046524.25369.7D Jen, 2005, Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures, Neurology, 65, 529, 10.1212/01.WNL.0000172638.58172.5a Ophoff, 1996, Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutation in the Ca2+ channel gene CACNL1A4, Cell, 87, 543, 10.1016/S0092-8674(00)81373-2 Joutel, 1993, A gene for familial hemiplegic migraine maps to chromosome 19, Nat Genet, 5, 40, 10.1038/ng0993-40 Battistini, 1999, A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia, Neurology, 53, 38, 10.1212/WNL.53.1.38 Carrera, 1999, Genetic heterogeneity in Italian families with familial hemiplegic migraine, Neurology, 53, 26, 10.1212/WNL.53.1.26 Ducros, 1999, Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia, Am J Hum Genet, 64, 89, 10.1086/302192 Friend, 1999, Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM, Hum Genet, 105, 261, 10.1007/s004399900101 Vahedi, 2000, CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy, Neurology, 55, 1040, 10.1212/WNL.55.7.1040 Ducros, 2001, The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel, N Engl J Med, 345, 17, 10.1056/NEJM200107053450103 Takahashi, 2002, Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNA1A gene, J Neurol Neurosurg Psychiatry, 72, 676, 10.1136/jnnp.72.5.676-a Terwindt, 2002, Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine, Arch Neurol, 59, 1016, 10.1001/archneur.59.6.1016 Wada, 2002, Wide clinical variability in a family with a CACNA1A T666m mutation: hemiplegic migraine, coma, and progressive ataxia, Pediatr Neurol, 26, 47, 10.1016/S0887-8994(01)00371-X Alonso, 2003, Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family, Arch Neurol, 60, 610, 10.1001/archneur.60.4.610 Kors, 2003, Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine, Arch Neurol, 60, 684, 10.1001/archneur.60.5.684 Alonso, 2004, A novel R1347Q mutation in the predicted voltage sensor segment of the P/Q-type calcium-channel alpha-subunit in a family with progressive cerebellar ataxia and hemiplegic migraine, Clin Genet, 65, 70, 10.1111/j..2004.00187.x Beauvais, 2004, New CACNA1A gene mutation in a case of familial hemiplegic migraine with status epilepticus, Eur Neurol, 52, 58, 10.1159/000079546 Kors, 2004, Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation, Neurology, 63, 1136, 10.1212/01.WNL.0000138571.48593.FC Zhuchenko, 1997, Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel, Nat Genet, 15, 62, 10.1038/ng0197-62 Kraus, 1998, Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics, J Biol Chem, 273, 5586, 10.1074/jbc.273.10.5586 Hans, 1999, Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine, J Neurosci, 19, 1610, 10.1523/JNEUROSCI.19-05-01610.1999 Kraus, 2000, Three new familial hemiplegic migraine mutants affect P/Q-type Ca2+ channel kinetics, J Biol Chem, 275, 9239, 10.1074/jbc.275.13.9239 Tottene, 2002, Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons, Proc Natl Acad Sci USA, 99, 13284, 10.1073/pnas.192242399 Melliti, 2003, The familial hemiplegic migraine mutation R192Q reduces G-protein-mediated inhibition of P/Q-type (Ca(V)2.1) calcium channels expressed in human embryonic kidney cells, J Physiol, 546, 337, 10.1113/jphysiol.2002.026716 Mullner, 2004, Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter Cav2.1 Ca2+ channel gating: evidence for beta-subunit isoform-specific effects, J Biol Chem, 279, 51844, 10.1074/jbc.M408756200 Tottene, 2005, Specific kinetic alterations of human CaV2.1 calcium channels produced by mutation S218L causing familial hemiplegic migraine and delayed cerebral edema and coma after minor head trauma, J Biol Chem, 280, 17678, 10.1074/jbc.M501110200 van den Maagdenberg, 2004, A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression, Neuron, 41, 701, 10.1016/S0896-6273(04)00085-6 Cao, 2004, Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy, Neuron, 43, 387, 10.1016/j.neuron.2004.07.014 Barrett, 2005, Gating deficiency in a familial hemiplegic migraine type 1 mutant P/Q-type calcium channel, J Biol Chem, 280, 24064, 10.1074/jbc.M502223200 Cao, 2005, Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission, Proc Natl Acad Sci USA, 102, 2590, 10.1073/pnas.0409896102 Ophoff, 1994, Genetic heterogeneity of familial hemiplegic migraine, Genomics, 22, 21, 10.1006/geno.1994.1340 Ducros, 1997, Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity, Ann Neurol, 42, 885, 10.1002/ana.410420610 Gardner, 1997, A new locus for hemiplegic migraine maps to chromosome 1q31, Neurology, 489, 1231, 10.1212/WNL.49.5.1231 Marconi, 2003, Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23, Ann Neurol, 53, 376, 10.1002/ana.10464 De Fusco, 2003, Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2, Nat Genet, 33, 192, 10.1038/ng1081 Vanmolkot, 2003, Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions, Ann Neurol, 54, 360, 10.1002/ana.10674 Gardner, 2004, A two-locus FHM2 family with unique ATP1A2 mutation and comparative study in C. elegans showing regulation of tryptophan hydroxylase by EAT-6 and UNC-2, the orthologous FHM2 and FHM1 genes, Cephalalgia, 24, 149 Jurkat-Rott, 2004, Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants, Neurology, 62, 1857, 10.1212/01.WNL.0000127310.11526.FD Kaunisto, 2004, A novel missense mutation in a Finnish family with familial hemiplegic migraine type 2, Neurogenetics, 5, 141, 10.1007/s10048-004-0178-z Spadaro, 2004, A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs, Neurogenetics, 5, 177, 10.1007/s10048-004-0183-2 Riant, 2005, ATP1A2 mutations in 11 families with familial hemiplegic migraine, Hum Mutat, 26, 281, 10.1002/humu.9361 Pierelli, 2006, A novel ATP1A2 mutation in a family with FHM type II, Cephalalgia, 26, 324, 10.1111/j.1468-2982.2006.01002.x Vanmolkot, 2006, Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation, Ann Neurol, 59, 310, 10.1002/ana.20760 Segall, 2005, Alterations in the alpha2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2, Proc Natl Acad Sci USA, 102, 11106, 10.1073/pnas.0504323102 Moseley, 2003, The Na,K-ATPase alpha 2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice, J Biol Chem, 278, 5317, 10.1074/jbc.M211315200 Ikeda, 2003, Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump alpha2 subunit (Atp1a2)-deficient mice, J Neurosci, 23, 4667, 10.1523/JNEUROSCI.23-11-04667.2003 Lingrel, 2003, Functional roles of the alpha isoforms of the Na,K-ATPase, Ann N Y Acad Sci, 986, 354, 10.1111/j.1749-6632.2003.tb07214.x Dichgans, 2005, Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine, Lancet, 5, 371, 10.1016/S0140-6736(05)66786-4 Meisler, 2005, Sodium channel mutations in epilepsy and other neurological disorders, J Clin Invest, 115, 2010, 10.1172/JCI25466 Hadjikhani, 2001, Mechanisms of migraine aura revealed by functional MRI in human visual cortex, Proc Natl Acad Sci USA, 98, 4687, 10.1073/pnas.071582498 Bolay, 2002, Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model, Nat Med, 8, 136, 10.1038/nm0202-136 Curtain, 2006, Minor head trauma-induced sporadic hemiplegic migraine coma, Pediatr Neurol, 34, 329, 10.1016/j.pediatrneurol.2005.08.033 Terwindt, 1998, Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine, Neurology, 50, 1105, 10.1212/WNL.50.4.1105 May, 1995, Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura, Hum Genet, 96, 604, 10.1007/BF00197420 Terwindt, 2001, Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura, Neurology, 56, 1028, 10.1212/WNL.56.8.1028 Hovatta, 1994, Familial migraine: exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p, Genomics, 23, 707, 10.1006/geno.1994.1563 Lea, 2001, Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility, Am J Med Genet, 105, 707, 10.1002/ajmg.1609 Noble-Topham, 2002, Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13, Neurology, 59, 1099, 10.1212/WNL.59.7.1099 Kaunisto, 2004, Chromosome 19p13 loci in Finnish migraine with aura families, Am J Med Genet B Neuropsychiatr Genet, 132, 85 Brugnoni, 2002, Is the CACNA1A gene involved in familial migraine with aura?, Neurol Sci, 23, 1, 10.1007/s100720200015 Wieser, 2003, Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing, Clin Chem Lab Med, 41, 272, 10.1515/CCLM.2003.042 Kirchmann, 2006, The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura, Am J Med Genet B Neuropsychiatr Genet, 141, 250, 10.1002/ajmg.b.30277 Jones, 2001, Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus, Genomics, 78, 150, 10.1006/geno.2001.6665 Curtain, 2006, No mutations detected in the INSR gene in a chromosome 19p13 linked migraine pedigree, Eur J Med Genet, 49, 57, 10.1016/j.ejmg.2005.01.015 Castro, 2004, A mutation in the ATP1A2 gene in a large family with migraine without aura, Am J Hum Genet, 382, 2089 Ambrosini, 2005, Familial basilar migraine associated with a new mutation in the ATP1A2 gene, Neurology, 65, 1826, 10.1212/01.wnl.0000187072.71931.c0 Todt, 2005, Rare missense variants in ATP1A2 in families with clustering of common forms of migraine, Hum Mutat, 26, 315, 10.1002/humu.20229 Jen, 2004, No mutations in CACNA1A and ATP1A2 in probands with common types of migraine, Arch Neurol, 61, 926, 10.1001/archneur.61.6.926 Netzer, 2006, Haplotype-based systematic association studies of ATP1A2 in migraine with aura, Am J Med Genet B Neuropsychiatr Genet, 141, 257, 10.1002/ajmg.b.30283 Hubner, 2002, Ion channel diseases, Hum Mol Genet, 20, 2435, 10.1093/hmg/11.20.2435 Colson, 2004, The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups, Neurogenetics, 5, 129, 10.1007/s10048-004-0181-4 Oterino, 2006, Association of migraine and ESR1 G325C polymorphism, Neuroreport, 17, 61, 10.1097/01.wnr.0000192735.85287.f4 Colson, 2005, Investigation of hormone receptor genes in migraine, Neurogenetics, 6, 17, 10.1007/s10048-004-0205-0 McCarthy, 2001, Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine, Genomics, 78, 135, 10.1006/geno.2001.6647 Lea, 2004, The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura, BMC Med, 2, 3, 10.1186/1741-7015-2-3 Scher, 2006, Migraine and MTHFR C677T genotype in a population-based sample, Ann Neurol, 59, 372, 10.1002/ana.20755 Rainero, 2004, Association between the tumor necrosis factor-alpha -308 G/A gene polymorphism and migraine, Neurology, 62, 141, 10.1212/01.WNL.0000101717.16799.8F Paterna, 2000, Angiotensin-converting enzyme gene deletion polymorphism determines an increase in frequency of migraine attacks in patients suffering from migraine without aura, Eur Neurol, 43, 133, 10.1159/000008151 Mochi, 2003, Investigation of an LDLR gene polymorphism (19p13.2) in susceptibility to migraine without aura, J Neurol Sci, 15, 7, 10.1016/S0022-510X(03)00124-2 Rainero, 2005, Association between migraine and HLA-DRB1 gene polymorphisms, J Headache Pain, 6, 185, 10.1007/s10194-005-0180-3 Palotie, 2002, Genetics of migraine, 935 Estevez, 2004, Update on the genetics of migraine, Hum Genet, 114, 225, 10.1007/s00439-003-1055-9 Kors, 2004, Recent findings in headache genetics, Curr Opin Neurol, 17, 283, 10.1097/00019052-200406000-00008 Ferrari, 2006, Genetics of migraine: CACNA1A with mutations, 251 Ogilvie, 1998, Altered allelic distributions of the serotonin transporter gene in migraine without aura and migraine with aura, Cephalalgia, 18, 23, 10.1046/j.1468-2982.1998.1801023.x Kowa, 2000, The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine, Am J Med Genet, 96, 762, 10.1002/1096-8628(20001204)96:6<762::AID-AJMG12>3.0.CO;2-X Kara, 2003, Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk, Molecular Brain Research, 111, 84, 10.1016/S0169-328X(02)00672-1 Oterino, 2004, MTHFR T677 homozygosis influences the presence of aura in migraineurs, Cephalalgia, 24, 491, 10.1111/j.1468-2982.2004.00692.x Kaunisto, 2006, Testing of variants of the MTHFR and ESR1 genes in 1798 Finnish individuals fails to confirm the association with migraine with aura, Cephalalgia, 26, 1462, 10.1111/j.1468-2982.2006.01228.x Todt, 2006, MTHFR C677T polymorphism and migraine with aura, Ann Neurol, 60, 621, 10.1002/ana.20911 2005, A haplotype map of the human genome, Nature, 437, 1299, 10.1038/nature04226 Gambaro, 2000, Association studies of genetic polymorphisms and complex disease, Lancet, 355, 308, 10.1016/S0140-6736(99)07202-5 Ioannidis, 2001, Replication validity of genetic association studies, Nat Genet, 29, 306, 10.1038/ng749 Ardlie, 2002, Testing for population subdivision and association in four case-control studies, Am J Hum Genet, 71, 304, 10.1086/341719 Freedman, 2004, Assessing the impact of population stratification on genetic association studies, Nat Genet, 36, 388, 10.1038/ng1333 Marchini, 2004, The effects of human population structure on large genetic association studies, Nat Genet, 36, 512, 10.1038/ng1337 Helgason, 2005, An Icelandic example of the impact of population structure on association studies, Nat Genet, 37, 90, 10.1038/ng1492 Davies, 1994, A genome-wide search for human type 1 diabetes susceptibility genes, Nature, 371, 130, 10.1038/371130a0 Carlsson, 2002, Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1, Neurology, 59, 1804, 10.1212/01.WNL.0000036617.04943.96 Wessman, 2002, A susceptibility locus for migraine with aura, on chromosome 4q24, Am J Hum Genet, 70, 652, 10.1086/339078 Björnsson, 2003, Localization of a gene for migraine without aura to chromosome 4q21, Am J Hum Genet, 73, 986, 10.1086/378417 Cader, 2003, Significant linkage to migraine with aura on chromosome 11q24, Hum Mol Genet, 12, 2511, 10.1093/hmg/ddg252 Soragna, 2003, A locus for migraine without aura maps on chromosome 14q21.2-q22.3, Am J Hum Genet, 72, 161, 10.1086/345298 Russell, 1995, Prevalence and sex-ratio of the subtypes of migraine, Int J Epidemiol, 24, 612, 10.1093/ije/24.3.612 Lea, 2005, A genome-wide scan provides evidence for loci influencing a severe heritable form of common migraine, Neurogenetics, 6, 67, 10.1007/s10048-005-0215-6 Nyholt, 2005, Genomewide significant linkage to migrainous headache on chromosome 5q21, Am J Hum Genet, 77, 500, 10.1086/444510 Anttila, 2006, Trait components provide tools to dissect the genetic susceptibility of migraine, Am J Hum Genet, 79, 85, 10.1086/504814 Nyholt, 1998, Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity, Neurology, 50, 1428, 10.1212/WNL.50.5.1428 Nyholt, 2000, Familial typical migraine: significant linkage and localization of a gene to Xq24-28, Hum Genet, 107, 18 Lea, 2002, A typical migraine susceptibility region localizes to chromosome 1q31, Neurogenetics, 4, 17, 10.1007/s10048-001-0125-1 Russo, 2005, A new susceptibility locus for migraine with aura in the 15q11-q13 genomic region containing three GABA-A receptor genes, Am J Hum Genet, 76, 327, 10.1086/427521 Altmuller, 2001, Genomewide scans of complex human diseases: true linkage is hard to find, Am J Hum Genet, 69, 936, 10.1086/324069 Pajukanta, 1998, Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23, Nat Genet, 18, 369, 10.1038/ng0498-369 Bouzigon, 2004, Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families, Hum Mol Genet, 13, 3103, 10.1093/hmg/ddh340 Hamet, 2005, Quantitative founder-effect analysis of French Canadian families identifies specific loci contributing to metabolic phenotypes of hypertension, Am J Hum Genet, 76, 815, 10.1086/430133 Gottesman, 2003, The endophenotype concept in psychiatry: etymology and strategic intentions, Am J Psychiatry, 160, 636, 10.1176/appi.ajp.160.4.636 Alarcon, 2002, Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families, Am J Hum Genet, 70, 60, 10.1086/338241 Paunio, 2004, Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q, Hum Mol Genet, 13, 1693, 10.1093/hmg/ddh184 McCutcheon, 1987, Sexual morality, pro-life values, and attitudes toward abortion: a simultaneous latent structure analysis for 1978–1983, Sociol Methods Res, 16, 256, 10.1177/0049124187016002003 Freedman, 1999, Alternative phenotypes for the complex genetics of schizophrenia, Biol Psychiatry, 45, 551, 10.1016/S0006-3223(98)00321-7 Almasy, 2001, Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design, Am J Med Genet, 105, 42, 10.1002/1096-8628(20010108)105:1<42::AID-AJMG1055>3.0.CO;2-9 Lifton, 2001, Molecular mechanisms of human hypertension, Cell, 104, 545, 10.1016/S0092-8674(01)00241-0