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1.  Parental social responsiveness and risk of autism spectrum disorder in offspring 
JAMA psychiatry  2014;71(8):936-942.
Although autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of sub-clinical autistic traits in non-clinical samples are poorly understood.
To determine the familiality of Social Responsiveness Scale (SRS) scores; we hypothesized that sub-clinical autistic traits would be associated in families.
Design and Setting
Nested case-control study within a population-based longitudinal cohort.
Participants were drawn from the Nurses’ Health Study II (NHS II), a cohort of 116,430 nurses. Cases were index children with reported ASD; controls were frequency matched by years of case births among those not reporting ASD. Of 3161 eligible participants, 2144 returned SRS forms for a child and at least one parent and were included in these analyses.
SRS scores, as reported by nurse participants/mothers and their spouses, were examined in association with liability to ASD using crude and adjusted logistic regression. Child SRS scores were examined in association with parental SRS scores using crude and adjusted linear regression, stratified by case status.
Main Outcome Measure
ASD, assessed by maternal report, validated in a subgroup with the Autism Diagnostic Interview-Revised.
1,649 individuals were included in these analyses, representing 256 ASD cases, 1,393 controls, 1,233 mothers and 1,614 fathers. Index child SRS scores confirmed reported diagnoses. We report for the first time in a large epidemiologic sample that elevated parental quantitative autism traits (QAT) index risk for clinical ASD among offspring. The effect was most pronounced for fathers and for spousal pairs concordant for QAT elevation, which occurred more often than predicted by chance, due to significant preferential mating for QAT. Elevated parent scores significantly increased child scores in controls, corresponding to an increase in approximately 20 points.
Conclusions and Relevance
These findings support the role of additive genetic influences in ASD, underscore the potential role of preferential mating in ASD population genetics, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits.
PMCID: PMC4126195  PMID: 25100167
2.  Maternal Dietary Fat Intake in Association With Autism Spectrum Disorders 
American Journal of Epidemiology  2013;178(2):209-220.
Our goal in this study was to determine whether maternal fat intake before or during pregnancy was associated with risk of autism spectrum disorder (ASD) in the offspring. Our primary analysis included 317 mothers who reported a child with ASD and 17,728 comparison mothers from the Nurses' Health Study II (index births in 1991–2007). Dietary information was collected prospectively through a validated food frequency questionnaire. Binomial regression was used to estimate crude and adjusted risk ratios. Maternal intake of linoleic acid was significantly inversely associated with ASD risk in offspring, corresponding to a 34% reduction in risk in the highest versus lowest quartiles of intake. Mothers in the lowest 5% of ω-3 fatty acid intake had a significant increase in offspring ASD risk as compared with the remaining distribution (risk ratio = 1.53, 95% confidence interval: 1.00, 2.32); this association was also seen in the subgroup of women (86 cases and 5,798 noncases) for whom dietary information during pregnancy was available (risk ratio = 2.42, 95% confidence interval: 1.19, 4.91). Thus, variations in intake of polyunsaturated fats within the range commonly observed among US women could affect fetal brain development and ASD risk. Because the number of women with diet assessed during pregnancy was small, however, these results should be interpreted cautiously.
PMCID: PMC3988447  PMID: 23813699
autism; dietary fat; linoleic acid; ω-3 fatty acids; ω-6 fatty acids; polyunsaturated fatty acids
3.  Common genetic variation in the GAD1 gene and the entire family of DLX homeobox genes and autism spectrum disorders 
Biological and positional evidence supports the involvement of the GAD1 and distal-less homeobox genes (DLXs) in the etiology of autism. We investigated 42 SNPs in these genes as risk factors for autism spectrum disorders (ASD) in a large family-based association study of 715 nuclear families. No single marker showed significant association after correction for multiple testing. A rare haplotype in the DLX1 promoter was associated with ASD (p-value = 0.001). Given the importance of rare variants to the etiology of autism revealed in recent studies, the observed rare haplotype may be relevant to future investigations. Our observations, when taken together with previous findings, suggest that common genetic variation in the GAD1 and DLX genes is unlikely to play a critical role in ASD susceptibility.
PMCID: PMC3088769  PMID: 21302352
Autism spectrum disorder; genetic association; candidate gene study; DLX homeobox; GAD1
4.  Fertility Therapies, Infertility and Autism Spectrum Disorders in the Nurses’ Health Study II 
An increasing number of women are utilizing fertility treatments, but little is known about their relation to autism spectrum disorders (ASD).
To determine the association between maternal fertility therapy use and risk of having a child with ASD, we conducted a nested case-control study within the Nurses’ Health Study II (n = 116,430). Maternally reported diagnoses of ASD were confirmed through a supplementary questionnaire and, in a subgroup, the Autism Diagnostic Interview-Revised. Controls were randomly selected by frequency matching to case children’s year of birth. Associations were examined by self-reported infertility and type of therapy using conditional logistic regression.
In all, 9% of the 507 cases and 7% of 2,529 controls indicated fertility therapy use for the index pregnancy. No significant associations with self-reported fertility therapies or history of infertility were seen in primary analyses. In subgroup analyses of women with maternal age ≥35 years (n = 1,020), artificial insemination was significantly associated with ASD; ovulation inducing drug (OID) use was significantly associated in crude but not adjusted analyses (odds ratio 1.81, 95% CI 0.96–3.42). Results were similar by diagnostic subgroup, though within the advanced maternal age group, OID and artificial insemination were significantly associated with Asperger syndrome and pervasive developmental disorder not-otherwise specified, but not autistic disorder.
Assisted reproductive therapy and history of infertility did not increase risk of having a child with ASD in this study. However, the associations observed with OID and artificial insemination among older mothers, for whom these exposures are more common, warrant further investigation.
PMCID: PMC3494409  PMID: 22686388
autism; infertility; fertility treatments; assisted reproductive technology (ART); ovulation-inducing drugs
5.  Pregnancy complications and obstetric suboptimality in association with autism spectrum disorders in children of the Nurses' Health Study II 
Autism Research  2011;5(1):21-30.
Scientific Abstract
The authors examined pregnancy and obstetric complications in association with autism spectrum disorders (ASD) in children of participants from the Nurses' Health Study II, a prospective national cohort with information collected through biennial mailed questionnaires since 1989. Logistic regression was used to obtain crude and adjusted odds ratios for ASD, and by diagnostic subgroup. 793 cases were reported among 66,445 pregnancies. Pregnancy complications and obstetric suboptimality factors were assessed by maternal report of occurrence in first birth and, in secondary analyses, in any birth. Complications and a suboptimality score were significantly associated with having a child with ASD (OR 1.49, 95% CI 1.26, 1.77, p <.0001 for pregnancy complications in first birth and 2.76, 95% CI 2.04, 3.74, p <.0001 comparing individuals with 4 or more obstetric suboptimality factors in first birth to those with none; results similar when assessed in any birth). In particular, gestational diabetes was associated with a significantly increased risk of ASD in results of primary and sensitivity analyses (OR in primary analysis = 1.76, 95% CI 1.34, 2.32, p <.0001); suboptimal parity and suboptimal age at first birth were also individual factors associated with ASD. Associations were similar by diagnostic subgroup, suggesting autism, Asperger syndrome, and other Pervasive Developmental Disorders are all associated with pregnancy complications. Consistent with previous research, the general class of pregnancy complications was associated with autism spectrum disorders as a whole. Additional work will be required to more fully assess the role of gestational diabetes.
PMCID: PMC3253333  PMID: 21972225
Autism Spectrum Disorders; Gestational Diabetes; Obstetric Labor Complications; Pregnancy Complications
6.  Brief Report: No Association Between Parental Age and Extreme Social-Communicative Autistic Traits in the General Population 
This is the first investigation of the relationship between parental age and extreme social-communicative autistic traits in the general population. The parents of 5,246 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) completed the Social and Communication Disorders Checklist (SCDC). The association between parental age and SCDC scores was assessed in the full sample and among high scoring individuals (e.g. top 5%, 1%). There was no association between parental age and social-communicative autistic traits in the general population. Neither maternal nor paternal age was associated with extreme scores. These findings suggest that advanced parental age does not confer increased risk for extreme social and communication impairment assessed quantitatively.
PMCID: PMC3160499  PMID: 21350918
Autism spectrum disorders; Autistic traits; arental age; ALSPAC
7.  A study of the prevalence and risk factors leading to HIV infection among a sample of street children and youth of Kathmandu 
The true prevalence of HIV and other sexually transmitted diseases among street children in Nepal is virtually unknown while information on related behavioural risk factors in this population is non-existent. The risk of HIV infection among street children and adolescents may be especially high due to their marginalized social and economic conditions. This study was conducted to determine the prevalence of HIV infection among a sample of street children and youth of Kathmandu and to identify risk factors associated with HIV infection in this group.
A sample of street children and youth was recruited based on the purposive sampling of ten streets in Kathmandu, Nepal, known to have a high density of street children and youth. A total of 251 street children (aged 11–16 years) and youth (aged 17–24 years) were enrolled, with informed consent, from November, 2008 through June, 2009. Most of the participants (95%) were male. Case status was determined by serological assessment of HIV status; data on risk factors were obtained using structured survey interviews. HIV prevalence and rates of a number of behavioural risk factors suspected to play a role in HIV transmission among street children and youth were determined, including unprotected sex, intravenous drug use, and other risky sex and substance use behaviours.
Among the 251 children and youth, we found an overall HIV prevalence of 7.6%. As the sample size of females was small (n = 13) and the behavioural risk factors are likely to be quite different for boys and girls, we conducted separate analyses by gender. As our small sample of females is unlikely to be representative and lacks power for statistical testing, our report focuses on the results for the males surveyed.The strongest behavioural risk factor to emerge from this study was intravenous drug use; 30% of the male subjects were injecting drug users and 20% of those were HIV positive. Furthermore, frequency of drug injection was a highly significant predictor with a dose–response relationship; males reporting occasional injection drug use were nearly 9 times more likely to be HIV positive than never users, while weekly drug injectors had over 46 times the risk of non-users, controlling for exposure to group sex, the only other significant risk factor in the multivariate model.
This sample of street children and youth of Kathmandu has a nearly 20-fold higher prevalence of HIV infection than the general population of Nepal (0.39%). The children and youth engage in number of high risk behaviours, including intravenous drug use, putting them at significant risk of contracting HIV and other sexually transmitted infections.
PMCID: PMC3472290  PMID: 22929124
HIV prevalence; Behavioural risk factors; Intravenous drug use; Street children; Kathmandu; Nepal
8.  Paternal age increases the risk for autism in an Iranian population sample 
Molecular Autism  2010;1:2.
Autism is a neurodevelopmental disorder which is known to have a strong genetic component and is most likely oligogenic. However, the necessary role of environmental factors has been well documented. Prior research suggests that parental characteristics, such as age and level of education, may be associated with a risk of autism. Parental age has been shown to be associated with many disorders, such as schizophrenia, childhood cancer and fetal death. However, results from studies of parental age and autism are inconsistent.
In the present study, we investigated the association of autism with parental age in 179 autism cases and 1611 matched cohort children from Iran. Each case was matched with nine cohort controls on parental education, sex, order of birth, consanguineous marriage, urbanism and province of residence. The Cox regression model was used to carry out conditional logistic regression on the matched data.
There was a significant association between higher paternal age, but not maternal age, and an increasing risk of autism. An analysis of the combined effect of parental age and education also revealed that parents with higher education had an increased risk of having autistic children, with a dose-response effect of parental age.
This study, which is the first epidemiological study of autism in Iran, provides evidence of the association of paternal age and risk of autism.
PMCID: PMC2907564  PMID: 20678245
9.  Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes 
BMC Medical Genetics  2004;5:12.
A substantial body of research supports a genetic involvement in autism. Furthermore, results from various genomic screens implicate a region on chromosome 7q31 as harboring an autism susceptibility variant. We previously narrowed this 34 cM region to a 3 cM critical region (located between D7S496 and D7S2418) using the Collaborative Linkage Study of Autism (CLSA) chromosome 7 linked families. This interval encompasses about 4.5 Mb of genomic DNA and encodes over fifty known and predicted genes. Four candidate genes (NRCAM, LRRN3, KIAA0716, and LAMB1) in this region were chosen for examination based on their proximity to the marker most consistently cosegregating with autism in these families (D7S1817), their tissue expression patterns, and likely biological relevance to autism.
Thirty-six intronic and exonic single nucleotide polymorphisms (SNPs) and one microsatellite marker within and around these four candidate genes were genotyped in 30 chromosome 7q31 linked families. Multiple SNPs were used to provide as complete coverage as possible since linkage disequilibrium can vary dramatically across even very short distances within a gene. Analyses of these data used the Pedigree Disequilibrium Test for single markers and a multilocus likelihood ratio test.
As expected, linkage disequilibrium occurred within each of these genes but we did not observe significant LD across genes. None of the polymorphisms in NRCAM, LRRN3, or KIAA0716 gave p < 0.05 suggesting that none of these genes is associated with autism susceptibility in this subset of chromosome 7-linked families. However, with LAMB1, the allelic association analysis revealed suggestive evidence for a positive association, including one individual SNP (p = 0.02) and three separate two-SNP haplotypes across the gene (p = 0.007, 0.012, and 0.012).
NRCAM, LRRN3, KIAA0716 are unlikely to be involved in autism. There is some evidence that variation in or near the LAMB1 gene may be involved in autism.
PMCID: PMC420465  PMID: 15128462
10.  A QTL genome scan of the metabolic syndrome and its component traits 
BMC Genetics  2003;4(Suppl 1):S96.
Because high blood pressure, altered lipid levels, obesity, and diabetes so frequently occur together, they are sometimes collectively referred to as the metabolic syndrome. While there have been many studies of each metabolic syndrome trait separately, few studies have attempted to analyze them combined, i.e., as one composite variable, in quantitative trait linkage or association analysis. We used genotype and phenotype data from the Framingham Heart Study to perform a full-genome scan for quantitative trait loci underlying the metabolic syndrome.
Heritability estimates for all of the covariate-adjusted and age- and gender-standardized individual traits, and the composite metabolic syndrome trait, were all fairly high (0.39–0.62), and the composite trait was among the highest at 0.61. The composite trait yielded no regions with suggestive linkage by Lander and Kruglyak's criteria, although there were several noteworthy regions for individual traits, some of which were also observed for the composite variable.
Despite its high heritability, the composite metabolic syndrome trait variable did not increase the power to detect or localize linkage peaks in this sample. However, this strategy and related methods of combining correlated individual traits deserve further investigation, particularly in settings with complex causal pathways.
PMCID: PMC1866537  PMID: 14975164

Results 1-10 (10)