A linkage disequilibrium map of the 1‐Mb 15q12 GABAA receptor subunit cluster and association to autism

American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics - Tập 131B Số 1 - Trang 51-59 - 2004
Jacob L. McCauley1, Lana M. Olson1, Ryan Delahanty1, Taneem Amin1, Michael S. Okun2, Edward L. Organ1, Michelle M. Jacobs2, Susan E. Folstein3, Jonathan L. Haines2,1, James S. Sutcliffe2,1
1Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Nashville, Tennessee
2Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee
3Department of Psychiatry, Tufts University and New England Medical Center, Boston, Massachusetts

Tóm tắt

AbstractAutism is a complex genetic neuropsychiatric condition characterized by deficits in social interaction and language and patterns of repetitive or stereotyped behaviors and restricted interests. Chromosome 15q11.2‐q13 is a candidate region for autism susceptibility based on observations of chromosomal duplications in a small percentage of affected individuals and findings of linkage and association. We performed linkage disequilibrium (LD) mapping across a 1‐Mb interval containing a cluster of GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) which are good positional and functional candidates. Intermarker LD was measured for 59 single nucleotide polymorphism (SNP) markers spanning this region, corresponding to an average marker spacing of 17.7 kb−1. We identified haplotype blocks, and characterized these blocks for common (>5%) haplotypes present in the study population. At this marker resolution, haplotype blocks comprise <50% of the DNA in this region, consistent with a high local recombination rate. Identification of haplotype tag SNPs reduces the overall number of markers necessary to detect all common alleles by only 12%. Individual SNPs and multi‐SNP haplotypes were examined for evidence of allelic association to autism, using a dataset of 123 multiplex autism families. Six markers individually, across GABRB3 and GABRA5, and several haplotypes inclusive of those markers, demonstrated nominally significant association. These results are positively correlated with the position of observed linkage. These studies support the existence of one or more autism risk alleles in the GABAA receptor subunit cluster on 15q12 and have implications for analysis of LD and association in regions with high local recombination. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website athttp://www.interscience.wiley.com/jpages/0148‐7299:1/suppmat/index.html. © 2004 Wiley‐Liss, Inc.

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Tài liệu tham khảo

10.1093/bioinformatics/16.2.182

10.1023/A:1022238706604

10.1038/sj.mp.4000708

10.1017/S0033291700028099

10.1023/A:1013238809666

10.1086/301624

10.1111/j.1469-8749.1994.tb11916.x

10.1038/sj.mp.4001011

10.1016/S0168-9525(03)00022-2

Cheng SD, 1994, Cytogenetic and molecular characterization of inverted duplicated chromosomes 15 from 11 patients, Am J Hum Genet, 55, 753

10.1002/ana.1003

10.1086/377138

10.1086/302577

10.1136/jmg.30.6.529

CLSA, 1999, An autosomal genomic screen for autism. Collaborative linkage study of autism, Am J Med Genet, 88, 609, 10.1002/(SICI)1096-8628(19991215)88:6<609::AID-AJMG7>3.0.CO;2-L

Cook EH, 1997, Autism or atypical autism in maternally but not paternally derived proximal 15q duplication, Am J Hum Genet, 60, 928

10.1086/301832

10.1038/ng1001-229

10.1038/nature00864

Dhossche D, 2002, Elevated plasma gamma‐aminobutyric acid (GABA) levels in autistic youngsters: Stimulus for a GABA hypothesis of autism, Med Sci Monit, 8, PR1

10.1002/(SICI)1096-8628(19960111)61:2<182::AID-AJMG17>3.0.CO;2-Q

Folstein SE, 1991, Etiology of autism: Genetic influences, Pediatrics, 87, 767, 10.1542/peds.87.5.767

10.1111/j.1469-7610.1977.tb00443.x

10.1017/S0033291799008508

10.1126/science.1069424

10.1006/geno.1997.4639

10.1093/hmg/7.3.571

10.1038/ng1001-217

10.1016/S0959-437X(98)80091-9

Kirkness EF, 1993, A strong promoter element is located between alternative exons of a gene encoding the human gamma‐aminobutyric acid‐type A receptor beta 3 subunit (GABRB3), J Biol Chem, 268, 4420, 10.1016/S0021-9258(18)53626-7

10.1038/ng917

10.1086/321980

10.1002/(SICI)1096-8628(19991015)88:5<492::AID-AJMG11>3.0.CO;2-X

10.1002/(SICI)1096-8628(20000207)96:1<43::AID-AJMG9>3.0.CO;2-3

10.1086/302957

10.3109/01677060109167380

10.1002/(SICI)1096-8628(19990212)82:4<294::AID-AJMG4>3.0.CO;2-U

Moreno‐Fuenmayor H, 1996, Plasma excitatory amino acids in autism, Investigacion Clinica, 37, 113

10.1006/geno.2001.6617

10.1097/01.CHI.0000046868.56865.0F

10.1126/science.1065573

10.1093/hmg/8.5.805

Pickles A, 1995, Latent‐class analysis of recurrence risks for complex phenotypes with selection and measurement error: A twin and family history study of autism, Am J Hum Genet, 57, 717

10.1086/302497

10.1007/s00439-002-0678-6

10.1159/000472386

10.1002/(SICI)1096-8628(19991015)88:5<551::AID-AJMG21>3.0.CO;2-#

10.1002/ajmg.10153

10.1086/367846

Sobel E, 1996, Descent graphs in pedigree analysis: Applications to haplotyping, location scores, and marker‐sharing statistics, Am J Hum Genet, 58, 1323

10.1111/j.1469-7610.1989.tb00254.x

10.1097/00004583-200302000-00021

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American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

Tập 131B Số 1

51-59

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