No association between a common single nucleotide polymorphism, rs4141463, in the <i>MACROD2</i> gene and autism spectrum disorder

Curran, Sarah; Bolton, Patrick; Rozsnyai, Kinga; Chiocchetti, Andreas G.; Klauck, Sabine M.; Duketis, Eftichia; Poustka, Fritz; Schlitt, Sabine; Freitag, Christine M.; Lee, Irene; Muglia, Pierandrea; Poot, Martin; Staal, Wouter; Jonge, Maretha; Ophoff, Roel A.; Lewis, Cathryn M.; Skuse, David; Mandy, William; Vassos, Evangelos; Fossdal, Ragnheiður; Magnússon, Páll; Hreidarsson, Stefán; Sæmundsen, Evald; Stefánsson, Hreinn; Stefánsson, Kāri; Collier, David

doi:10.1002/ajmg.b.31201

Cited by 30 publications

(26 citation statements)

References 46 publications

(51 reference statements)

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“…This may be due to population effects, such as different allele compositions, or to limited power afforded by too small numbers of participants. The first possible explanation is consistent with the associating SNP rs1718101 in intron 1 found in the AGP cohort of ASD patients [Anney et al, 2012], with the SNPs rs2710093 and rs2253031 in intron 14 [Sampath et al, 2013], and the differences among different European populations reported with SNP rs4141463 in MACROD2 [Curran et al, 2011;Anney et al, 2012;Prandini et al, 2012].…”

Section: Association Of Cntnap2 With Neurodevelopmental Disorderssupporting

confidence: 78%

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

Poot¹

2015

Mol Syndromol

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Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.

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Section: Association Of Cntnap2 With Neurodevelopmental Disorderssupporting

confidence: 78%

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

Poot¹

2015

Mol Syndromol

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“…Curran et al (2011) attempted to replicate the association using an independent case–control design with 1170 European cases and 35 307 controls and Prandini et al (2012) sought to replicate genetic markers from recent genomewide and candidate-gene studies in the Italian Autism Network cohort, consisting of 233 probands, 423 parents, and 90 siblings. In both studies, cases met the Diagnostic and Statistical Manual of Mental Disorders, 4th ed.…”

Section: Discussionmentioning

confidence: 99%

MACROD2 gene associated with autistic-like traits in a general population sample

Jones

Cadby

Blangero

et al. 2014

Psychiatric Genetics

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There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0 × 10−5. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.

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“…The drive for large samples, notably in molecular genetics research, has encouraged the combination of data collected in different countries and languages (e.g. Curran et al, 2011). The question of whether ASD presents differently in different cultures has never been more pressing or more amenable to empirical investigation.…”

Section: Autism 18(1)mentioning

confidence: 99%

Investigating the cross-cultural validity of DSM-5 autism spectrum disorder: Evidence from Finnish and UK samples

Mandy¹,

Charman

Puura

et al. 2013

Autism

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The recent Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition (DSM-5) reformulation of autism spectrum disorder has received empirical support from North American and UK samples. Autism spectrum disorder is an increasingly global diagnosis, and research is needed to discover how well it generalises beyond North America and the United Kingdom. We tested the applicability of the DSM-5 model to a sample of Finnish young people with autism spectrum disorder (n = 130) or the broader autism phenotype (n = 110). Confirmatory factor analysis tested the DSM-5 model in Finland and compared the fit of this model between Finnish and UK participants (autism spectrum disorder, n = 488; broader autism phenotype, n = 220). In both countries, autistic symptoms were measured using the Developmental, Diagnostic and Dimensional Interview. Replicating findings from English-speaking samples, the DSM-5 model fitted well in Finnish autism spectrum disorder participants, outperforming a Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition (DSM-IV) model. The DSM-5 model fitted equally well in Finnish and UK autism spectrum disorder samples. Among broader autism phenotype participants, this model fitted well in the United Kingdom but poorly in Finland, suggesting that cross-cultural variability may be greatest for milder autistic characteristics. We encourage researchers with data from other cultures to emulate our methodological approach, to map any cultural variability in the manifestation of autism spectrum disorder and the broader autism phenotype. This would be especially valuable given the ongoing revision of the International Classification of Diseases–11th Edition, the most global of the diagnostic manuals.

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No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder

Cited by 30 publications

References 46 publications

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

MACROD2 gene associated with autistic-like traits in a general population sample

Investigating the cross-cultural validity of DSM-5 autism spectrum disorder: Evidence from Finnish and UK samples

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