Beta2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Molecular Psychiatry (Impact Factor: 14.5). 04/2007; 12(3):283-91. DOI: 10.1038/
Source: PubMed


The beta2-adrenergic receptor is part of the catecholamine system, and variants at two polymorphic sites in the gene coding for the receptor (ADRB2) confer increased activity. Overstimulation of this receptor may alter brain development, and has been linked to autism in non-identical twins. The objective of this study was to determine whether alleles in ADRB2 are associated with diagnosis of autism in the Autism Genetic Resource Exchange (AGRE) population. Three hundred and thirty-one independent autism case-parent trios were included in the analysis. Subjects were genotyped at activity-related polymorphisms rs1042713 (codon 16) and rs1042714 (codon 27). Association between autism and genotypes at each polymorphic site was tested using genotype-based transmission disequilibrium tests, and effect modification by family and pregnancy characteristics was evaluated. Sensitivity to designation of the proband in each family was assessed by performing 1000 repeats of the analysis selecting affected children randomly. A statistically significant OR of 1.66 for the Glu27 homozygous genotype was observed. Increased associations with this genotype were observed among a subset of Autism Diagnostic Observation Schedule confirmed cases and a subset reporting experience of pregnancy-related stressors. In conclusion, the Glu27 allele of the ADRB2 gene may confer increased risk of autism and shows increased strength with exposure to pregnancy related stress.

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    • "Previous studies have shown that the ADRB2 gene is associated with both longevity and specific psychological health outcomes; carriers are less likely to have panic disorder [9], hostility [10], psychomotor agitation [11], tension-anxiety [12], and depression [13]. The alleles of the ADRB2 gene have recently been associated with autism in child twins [14] as well as in the Autism Genetic Resource Exchange (AGRE) cohort [15]. The β2-adrenergic receptor has also been found to be associated with Alzheimer’s disease [16,17]. "
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    ABSTRACT: Existing literature indicates that ADRB2 gene is associated with health and longevity, but none of previous studies investigated associations of carrying the ADRB2 minor alleles and interactions between ADRB2 genotypes and social/behavioral factors(GxE) with health outcomes at advanced ages. This study intends to fill in this research gap. We conducted an exploratory analysis, using longitudinal survey phenotype/genotype data from 877 oldest-old aged 90+. To estimate association of GxE interactions with health outcome, adjusted for the potential correlation between genotypes and social/behavioral factors and various other potentially confounding factors, we develop and test an innovative three-step procedure which combines logistic regression and structural equation methods. Interaction between regular exercise and carrying rs1042718 minor allele is significantly and positively associated with good cognitive function; interaction between regular exercise and carrying rs1042718 or rs1042719 minor allele is significantly and positively associated with self-reported good health; and interaction between social-leisure activities and carrying rs1042719 minor allele is significantly and positively associated with self-reported good health. Carrying rs1042718 or rs1042719 minor alleles is significantly and negatively associated with negative emotion, but the ADRB2 SNPs are not significantly associated with cognitive function and self-reported health. Our structural equation analysis found that, adjusted for the confounding effects of correlation of the ADRB2 SNPs with negative emotion, interaction between negative emotion and carrying rs1042718 or rs1042719 minor allele is significantly and negatively associated with cognitive function. The positive association of regular exercise and social-leisure activities with cognitive function and self-reported health, and negative association of negative emotion with cognitive function, were much stronger among carriers of rs1042718 or rs1042719 alleles, compared to the non-carriers. The results indicate significant positive associations of interactions between social/behavioral factors and the ADRB2 genotypes with health outcomes of cognitive function and self-reported health, and negative associations of carrying rs1042718 or rs1042719 minor alleles with negative emotion, at advanced ages in China. Our findings are exploratory rather than causal conclusions. This study implies that near-future health promotion programs considering individuals' genetic profiles, with appropriate protection of privacy/confidentiality, would yield increased benefits and reduced costs to the programs and their participants.
    BMC Geriatrics 09/2013; 13(1):91. DOI:10.1186/1471-2318-13-91 · 1.68 Impact Factor
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    • "Evaluation of genotypic subgroups may also be important in fully understanding the effects of maternal exposure to B2AR agonists. Of note, variants at two polymorphic sites on the B2AR gene whose function is believed to be related to increased responsiveness of the receptor to ligand have been associated preliminarily with autism risk (Connors et al. 2005; Cheslack-Postava et al. 2007). In our study, genetic data were not available and there was no way to investigate whether B2AR exposure effects might have been stronger in subgroups defined by genotype. "
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    ABSTRACT: This study aims to investigate the association between prenatal exposure to terbutaline and other β2 adrenergic receptor (B2AR) agonists and autism spectrum disorders (ASDs). The methodology used is a case-control study among children born from 1995 to 1999 at Kaiser Permanente Northern California hospitals. Cases (n = 291) were children with an ASD diagnosis; controls (n = 284) were children without ASDs, randomly sampled and frequency-matched to cases on sex, birth year, and delivery hospital. Exposure to B2AR agonists during 30 days prior to conception and each trimester of pregnancy was ascertained from prenatal medical records and health plan databases. The frequency of exposure to any B2AR agonist during pregnancy was similar for mothers of children with ASD and mothers of controls (18.9% vs. 14.8%, P = 0.19). Exposure to B2AR agonists other than terbutaline was not associated with an increased risk for ASDs. However, terbutaline exposure for >2 days during the third trimester was associated with more than a fourfold increased risk for ASDs independent of indication although the limited sample size resulted in an imprecise and nonsignificant effect estimate (OR(adj) = 4.4; 95% confidence interval, 0.8-24.6). This analysis does not offer evidence linking B2AR exposure in pregnancy with autism risk. However, exposure to terbutaline during the third trimester for >2 days may be associated with an increased risk of autism. Should this result be confirmed in larger samples, it would point to late pregnancy as an etiologic window of interest in autism risk factor research.
    Journal of Neurodevelopmental Disorders 08/2011; 3(4):307-15. DOI:10.1007/s11689-011-9093-4 · 3.27 Impact Factor
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    • "ADRB2, the beta-2 adrenergic receptor, is a G protein-coupled receptor that is expressed ubiquitously and influences many path­ ological states including asthma, obesity and Type 2 diabetes. The Glu27 allele of ADRB2 been associated with autism [43] in the AGRE [44] cohort as well as in dizygotic twins [45]. This polymor­ phism of ADRB2 is also associated with asthma disease severity and drug response [46]. "
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    ABSTRACT: Autism and autism spectrum disorders are enigmatic conditions that have their origins in the interaction of genes and environmental factors. In this hypothesis, genes statistically associated with autism are emphasized to be important in inflammation and in innate immune pathways, including pathways for susceptibility to asthma. The role of acetaminophen (paracetamol) in an increased risk for asthma is described and a possible similar link to an increased risk for autism is suggested. (C) Published by Elsevier Ltd.
    Medical Hypotheses 09/2009; 74(1):7-11. DOI:10.1016/j.mehy.2009.08.033 · 1.07 Impact Factor
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