No Association Between a Common Single Nucleotide Polymorphism, rs4141463, in the MACROD2 Gene and Autism Spectrum Disorder

Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Kings College London, UK.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 09/2011; 156B(6):633-9. DOI: 10.1002/ajmg.b.31201
Source: PubMed


The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism.

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    • "This further underscores the complex genomic architecture of ASD. Large-scale genome-wide association studies have detected common variants in genes such as CDH9, CDH10, NRXN1 and others, which often could not be independently replicated [Autism Genome Project Consortium et al., 2007; Ma et al., 2009; Wang et al., 2009; Curran et al., 2011]. Overall, individual common variants exert weak effects on the risk for ASD [Anney et al., 2012] but by acting additively may explain as much as 60% of the narrow-sense heritability in ASD individuals from multiplex families and approximately 40% for simplex families [Klei et al., 2012]. "
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    ABSTRACT: Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the CNTN5 gene (rs6590473 [G], p = 4.09 × 10(-7); OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in CNTN6 (rs9878022 [A]; OR = 3.749) and in CNTNAP2 (rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.
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    • "Similarly in ASD, GWAS on common genetic variants (SNPs) have not yielded independently replicated positive results (Devlin et al. 2011), although a few suggestive risk alleles with small effect sizes have been reported on 5p15 [mapping semaphorin 5A (SEMA5A) and the taste receptor, type 2, member 1 genes (TAS2R1) (Weiss et al. 2009)] and on 5p14.1, the region between CDH10 and CDH9 (coding for neuronal cell adhesion molecules of the above named cadherin family (Ma et al. 2009; Wang et al. 2009)). Furthermore , on chromosome 20p12.1 association with a SNP in the MACRO domain containing 2 gene (MACROD2) (Anney et al. 2010) was observed but not replicated (Curran et al. 2011). MACROD2 codes for a protein important in numerous biological processes, among others axonal outgrowth and metabotropic glutamate receptor signaling (Devlin et al. 2011). "
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    ABSTRACT: According to DSM-IV TR and ICD-10, a diagnosis of autism or Asperger Syndrome precludes a diagnosis of attention-deficit/hyperactivity disorder (ADHD). However, despite the different conceptualization, population-based twin studies reported symptom overlap, and a recent epidemiologically based study reported a high rate of ADHD in autism and autism spectrum disorders (ASD). In the planned revision of the DSM-IV TR, dsm5 (, the diagnoses of autistic disorder and ADHD will not be mutually exclusive any longer. This provides the basis of more differentiated studies on overlap and distinction between both disorders. This review presents data on comorbidity rates and symptom overlap and discusses common and disorder-specific risk factors, including recent proteomic studies. Neuropsychological findings in the areas of attention, reward processing, and social cognition are then compared between both disorders, as these cognitive abilities show overlapping as well as specific impairment for one of both disorders. In addition, selective brain imaging findings are reported. Therapeutic options are summarized, and new approaches are discussed. The review concludes with a prospectus on open questions for research and clinical practice.
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    • "Thus, whether SNPs in MACROD2 or in its intra-genic antisense RNA genes play a role in the risk for ASD remains an open question. If they do, however, there can now be little doubt that their effect size is modest on the basis of our results and others (24). "
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    ABSTRACT: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
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