An Analysis Paradigm for Investigating Multi‐locus Effects in Complex Disease: Examination of Three GABA_A Receptor Subunit Genes on 15q11‐q13 as Risk Factors for Autistic Disorder.

Abstract

SummaryGene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABA A receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three twomarker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…[213][214][215][216] Only nominal significant associations of different haplotypes, SNPs or microsatellites located in or around the GABRB3 and the GABRG3 gene have been found in three further studies. 215,[217][218][219] The largest study to date assessing GABA receptor subunit genes found evidence for association of a single SNP in the GABRA4 gene on chromosome 4p with AD, and for interaction effects of this variant with a SNP in the GABRB1 gene on chromosome 4p. No association for SNPs in the GABA receptor genes on chromosome 15 were found.…”

A Genome‐wide Scan in an Amish Pedigree with Parkinsonism

“…The pedigree was constructed using Cyrillic 2.1 (http://www.cyrillicsoftware.com). The recruitment and ascertainment methods were previously applied successfully in an Alzheimer disease study in the Amish (PericakVance et al 1996), (Ashley-Koch et al 2006).…”

No evidence for significant association between GABA receptor genes in chromosome 15q11–q13 and autism in a Japanese population

“…Two of the studies (Cook et al 1998;Buxbaum et al 2002) observed the association of a microsatellite located in intron 3 of GABRB3 (155CA-2), whereas the other four studies did not replicate the association (Salmon et al 1999;Maestrini et al 1999;Martin et al 2000;Curran et al 2005). Except for 155CA-2, only nominal significant associations were observed with respect to markers located in or around these three GABA receptor genes (Martin et al 2000;Menold et al 2001;McCauley et al 2004;Ashley-Koch et al 2006). In another three studies, no significant association was observed between the genes and autism (Nurmi et al 2001;Ma et al 2005;Kim et al 2006).…”