Association of Sex With Recurrence of Autism Spectrum Disorder Among Siblings

Palmer, Nathan; Beam, Andrew L.; Agniel, Denis; Eran, Alal; Manrai, Arjun K.; Spettell, Claire M.; Steinberg, Gregory; Mandl, Kenneth D.; Fox, Kathe; Nelson, Stanley F.; Kohane, Isaac S.

doi:10.1001/jamapediatrics.2017.2832

Cited by 81 publications

(67 citation statements)

References 25 publications

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“…In light of the evidence that most psychiatric disorders are multifactorial and polygenic, investigation of sex differences in transmission can be accomplished through application of the general multifactorial model of disease transmission, shown in of ASD has been attributed to the higher tolerance for mutational burden in females that has a protective influence on the development of ASD. 82,83 Evidence for this female-protective effect in ASD has been showed in population-based, 84 family-based, [85][86][87] and cohort studies. 88 The female-protective effect has also been shown in ADHD, 89 and may also apply to schizophrenia.…”

Section: Genetic Attributable Riskmentioning

confidence: 96%

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Merikangas

Almasy

2020

Genes Brain and Behavior

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Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X-or Ylinked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome-wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large-scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome-wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.

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Section: Genetic Attributable Riskmentioning

confidence: 96%

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Merikangas

Almasy

2020

Genes Brain and Behavior

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“…It is thought that advanced paternal age increases the risk of autism (pooled adjusted odds ratio 1.55, 95% confidence interval 1.39 to 1.73) by increasing rates of de novo mutations and epigenetic alterations 60. Additionally, sex has been found to interact with heritability where female probands had a greater recurrence risk than male probands (16.7% versus 12.9%) 6162. Female probands were also found to have an excess of deleterious autosomal copy number variants across several neurodevelopmental conditions including autism (odds ratio 1.46, calculated confidence interval 1.16 to 1.81) 34.…”

Section: Risk Factorsmentioning

confidence: 99%

Linking risk factors and outcomes in autism spectrum disorder: is there evidence for resilience?

Elsabbagh

2020

BMJ

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Autism spectrum disorder (referred to here as autism) is one of several overlapping neurodevelopmental conditions that have variable impacts on different individuals. This variability results from dynamic interactions between biological and non-biological risk factors, which result in increasing differentiation between individuals over time. Although this differentiation continues well into adulthood, the infancy period is when the brain and behavior develop rapidly, and when the first signs and symptoms of autism emerge. This review discusses advances in our understanding of the causal pathways leading to autism and overlapping neurodevelopmental conditions. Research is also mapping trajectories of brain and behavioral development for some risk groups, namely later born siblings of children with autism and/or infants referred because of developmental concerns. This knowledge has been useful in improving early identification and establishing the feasibility of targeted interventions for infant risk groups before symptoms arise. However, key knowledge gaps remain, such as the discovery of protective factors (biological or environmental) that may mitigate the impact of risk. Also, the dynamic mechanisms that underlie the associations between risk factors and outcomes need further research. These include the processes of resilience, which may explain why some individuals at risk for autism achieve better than expected outcomes. Bridging these knowledge gaps would help to provide tools for early identification and intervention that reflect dynamic developmental pathways from risk to outcomes.

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“…not on sex chromosomes), indicating that the universally-observed sex ratio in autism arises from mechanisms other than sex linkage. The inference from a vast amount of family recurrence and molecular genetic data that has accumulated to date is that most —but not all—females are relatively ‘protected’ from most —but not all—inherited forms of autism ( Constantino, 2016 ; Constantino et al, 2010 ; Jacquemont et al, 2014 ; Palmer et al, 2017 ). This suggests at least one highly parsimonious resiliency factor that operates against numerous genetic liabilities to ASD.…”

Section: Introductionmentioning

confidence: 99%

Deconstructing autism: from unitary syndrome to contributory developmental endophenotypes

Constantino

2018

International Review of Psychiatry

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A recent generation of family studies has revealed that autism can be predicted from an array of neurobehavioural susceptibilities that are appreciable before the syndrome is diagnosed, and that each may be traceable to partially-independent sets of genetic variation. Some of these liabilities are not necessarily specific to ASD—those that are non-specific could account for a significant share of the ‘missing heritability’ of autism, would (by definition) contribute to pleiotropy, and relate to so-called ‘co-morbidities’, which are inappropriately named if they actually contribute to (or exacerbate) the severity of autism itself. Linking genetic variants to these underlying traits rather than to a diagnosis of ‘autism’ may be more productive in devising personalized approaches to developmental intervention, especially if autism represents an epiphenomenon of earlier-interacting susceptibilities. In this article, the implications of conceptualizing autism as a syndrome of neurobehavioural degeneration is considered, predicated on the notion that it can arise from a critical co-aggregation of earlier-interacting neuropsychiatric liabilities, the phenotypic expression of which—importantly—can be moderated by sex.

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Association of Sex With Recurrence of Autism Spectrum Disorder Among Siblings

Cited by 81 publications

References 25 publications

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Linking risk factors and outcomes in autism spectrum disorder: is there evidence for resilience?

Deconstructing autism: from unitary syndrome to contributory developmental endophenotypes

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