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      Parental and Grandparental Ages in the Autistic Spectrum Disorders: A Birth Cohort Study

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      PLoS ONE
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          Abstract

          Background

          A number of studies have assessed ages of parents of children with autistic spectrum disorders (ASD), and reported both maternal and paternal age effects. Here we assess relationships with grandparental ages.

          Methods and Findings

          We compared the parental and grandparental ages of children in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC), according to their scores in regard to 4 autistic trait measures and whether they had been given a diagnosis of ASD. Mean maternal and paternal ages of ASD cases were raised, but this appears to be secondary to a maternal grandmother age effect (P = 0.006): OR = 1.66[95%CI 1.16, 2.37] for each 10-year increase in the grandmother's age at the birth of the mother. Trait measures also revealed an association between the maternal grandmother's age and the major autistic trait–the Coherence Scale (regression coefficient b = 0.142, [95%CI = 0.057, 0.228]P = 0.001). After allowing for confounders the effect size increased to b = 0.217[95%CI 0.125, 0.308](P<0.001) for each 10 year increase in age.

          Conclusions

          Although the relationship between maternal grandmother's age and ASD and a major autistic trait was unexpected, there is some biological plausibility, for the maternal side at least, given that the timing of female meiosis I permits direct effects on the grandchild's genome during the grandmother's pregnancy. An alternative explanation is the meiotic mismatch methylation (3 M) hypothesis, presented here for the first time. Nevertheless the findings should be treated as hypothesis generating pending corroborative results from other studies.

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          Most cited references20

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          Structural variation of chromosomes in autism spectrum disorder.

          Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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            ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology.

            ALSPAC (The Avon Longitudinal Study of Parents and Children, formerly the Avon Longitudinal Study of Pregnancy and Childhood) was specifically designed to determine ways in which the individual's genotype combines with environmental pressures to influence health and development. To date, there are comprehensive data on approximately 10,000 children and their parents, from early pregnancy until the children are aged between 8 and 9. The study aims to continue to collect detailed data on the children as they go through puberty noting, in particular, changes in anthropometry, attitudes and behaviour, fitness and other cardiovascular risk factors, bone mineralisation, allergic symptoms and mental health. The study started early during pregnancy and collected very detailed data from the mother and her partner before the child was born. This not only provided accurate data on concurrent features, especially medication, symptoms, diet and lifestyle, attitudes and behaviour, social and environmental features, but was unbiased by parental knowledge of any problems that the child might develop. From the time of the child's birth many different aspects of the child's environment have been monitored and a wide range of phenotypic data collected. By virtue of being based in one geographic area, linkage to medical and educational records is relatively simple, and hands-on assessments of children and parents using local facilities has the advantage of high quality control. The comprehensiveness of the ALSPAC approach with a total population sample unselected by disease status, and the availability of parental genotypes, provides an adequate sample for statistical analysis and for avoiding spurious results. The study has an open policy in regard to collaboration within strict confidentiality rules.
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              Common genetic variants on 5p14.1 associate with autism spectrum disorders.

              Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                1 April 2010
                : 5
                : 4
                : e9939
                Affiliations
                [1]Centre for Child and Adolescent Health, Department of Community Based Medicine, University of Bristol, Bristol, United Kingdom
                University of Louisville, United States of America
                Author notes

                Conceived and designed the experiments: JG CDS MP. Performed the experiments: JG MP. Analyzed the data: CDS. Wrote the paper: JG CDS MP.

                Article
                09-PONE-RA-14220R1
                10.1371/journal.pone.0009939
                2848579
                20376340
                2e9c83c5-fd6a-4019-8184-0da4627b7a24
                Golding et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 12 November 2009
                : 24 February 2010
                Page count
                Pages: 9
                Categories
                Research Article
                Pediatrics and Child Health/Child Development
                Pediatrics and Child Health/Developmental and Pediatric Neurology
                Public Health and Epidemiology/Epidemiology

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                Uncategorized

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