Abstract
The γ-aminobutyric acid (GABA) receptor genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11–q13 have been major candidates for susceptibility genes for autism, a neurodevelopmental disorder with a complex genetic etiology. In this study, we first investigated the association between the GABA receptor genes and autism in a Japanese population by analyzing 11 single nucleotide polymorphisms (SNPs). Intron 3 of GABRB3 was densely mapped because the previous studies observed the association of the microsatellite 155CA-2 located in the region. We observed no significant difference in allelic frequencies or genotypic distributions of the 11 SNPs between patients and controls. A permutation test showed no significant global differences in estimated haplotype frequencies between patients and controls. Analysis after confining the subjects to males showed similar results. Thus, this study provides no positive evidence of an association between the GABA receptor genes and autism in a Japanese population. However, in a SNP (rs3212337) located near the microsatellite 155CA-2, a significant deviation from the Hardy–Weinberg equilibrium was observed in patients (p = 0.029, corrected for multiple testing). This finding may suggest further studies around the markers for more definitive conclusions.
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Ashley-Koch AE, Mei H, Jaworski J, Ma DQ, Ritchie MD, Menold MM, Delong GR, Abramson RK, Wright HH, Hussman JP, Cuccaro ML, Gilbert JR, Martin ER, Pericak-Vance MA (2006) An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11–q13 as risk factors for autistic disorder. Ann Hum Genet 70:281–292
Blatt GJ, Fitzgerald GM, Guptill JT, Booker AB, Kemper TL, Bauman ML (2001) Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord 31:537–543
Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr, Fang Y, Song CY, Vitale R (2002) Association between a GABRB3 polymorphism and autism. Mol Psychiatry 7:311–316
Chong SS, Eichler EE, Nelson DL, Hughes MR (1994) Robust amplification and ethidium-visible detection of the fragile X syndrome CGG repeat using Pfu polymerase. Am J Med Genet 51:522–526
Cook EH Jr, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ, Lincoln A, Nix K, Haas R, Leventhal BL, Courchesne E (1998) Linkage-disequilibrium mapping of autistic disorder, with 15q11–13 markers. Am J Hum Genet 62:1077–1083
Curran S, Roberts S, Thomas S, Veltman M, Browne J, Medda E, Pickles A, Sham P, Bolton PF (2005) An association analysis of microsatellite markers across the Prader-Willi/Angelman critical region on chromosome 15 (q11–13) and autism spectrum disorder. Am J Med Genet 137B:25–28
Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927
Fallin D, Cohen A, Essioux L, Chumakov I, Blumenfeld M, Cohen D, Schork NJ (2001) Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer’s disease. Genome Res 11:143–151
Folstein SE, Rosen-Sheidley B (2001) Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2:943–955
Freitag CM (2007) The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry 12:2–22
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229
Honda H, Shimizu Y, Misumi K, Niimi M, Ohashi Y (1996) Cumulative incidence and prevalence of childhood autism in children in Japan. Br J Psychiatry 169:228–235
Hussman JP (2001) Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. J Autism Dev Disord 31:247–248
Izutsu T, Osada H, Tachimori H, Naganuma Y, Kato S, Kurita H (2001) The usefulness of the child behavior questionnaire revised (CBQ-R) as a supplementary scale for diagnosis of pervasive developmental disorders. Rinsyo-Seishin Igaku 30:525–532 (Japanese)
Kim SA, Kim JH, Park M, Cho IH, Yoo HJ (2006) Association of GABRB3 polymorphisms with autism spectrum disorders in Korean trios. Neuropsychobiology 54:160–165
Lewontin RC (1964) The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 120:849–852
Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA (2005) Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet 77:377–388
Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco AP, the International Molecular Genetics Study of Autism (IMGSA) Consortium (1999) Serotonin transporter (5-HTT) and γ-aminobutyric acid receptor subunit β3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet 88:492–496
Martin ER, Menold MM, Wolpert CM, Bass MP, Donnelly SL, Ravan SA, Zimmerman A, Gilbert JR, Vance JM, Maddox LO, Wright HH, Abramson RK, DeLong GR, Cuccaro ML, Pericak-Vance MA (2000) Analysis of linkage disequilibrium in γ-aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet 96:43–48
McCauley JL, Olson LM, Delahanty R, Amin T, Nurmi EL, Organ EL, Jacobs MM, Folstein SE, Haines JL, Sutcliffe JS (2004) A linkage disequilibrium map of the 1-Mb 15q12 GABAA receptor subunit cluster and association to autism. Am J Med Genet 131B:51–59
Menold MM, Shao Y, Wolpert CM, Donnelly SL, Raiford KL, Martin ER, Ravan SA, Abramson RK, Wright HH, Delong GR, Cuccaro ML, Pericak-Vance MA, Gilbert JR (2001) Association analysis of chromosome 15 GABAA receptor subunit genes in autistic disorder. J Neurogenet 15:245–259
Nurmi EL, Bradford Y, Chen YH, Hall J, Arnone B, Gardiner MB, Hutcheson HB, Gilbert JR, Pericak-Vance MA, Copeland-Yates SA, Michaelis RC, Wassink TH, Santangelo SL, Sheffield VC, Piven J, Folstein SE, Haines JL, Sutcliffe JS (2001) Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics 77:105–113
Salmon B, Hallmayer J, Rogers T, Kalaydjieva L, Petersen PB, Nicholas P, Pingree C, McMahon W, Spiker D, Lotspeich L, Kraemer H, McCague P, Dimiceli S, Nouri N, Pitts T, Yang J, Hinds D, Myers RM, Risch N (1999) Absence of linkage and linkage disequilibrium to chromosome 15q11–q13 markers in 139 multiplex families with autism. Am J Med Genet 88:551–556
Wang N, Akey JM, Zhang K, Chakraborty R, Jin L (2002) Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am J Hum Genet 71:1227–1234
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Tochigi, M., Kato, C., Koishi, S. et al. No evidence for significant association between GABA receptor genes in chromosome 15q11–q13 and autism in a Japanese population. J Hum Genet 52, 985–989 (2007). https://doi.org/10.1007/s10038-007-0207-5
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DOI: https://doi.org/10.1007/s10038-007-0207-5
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