Autism Risk Across Generations

Frans, Emma M.; Sandin, Sven; Reichenberg, Abraham; Långström, Niklas; Lichtenstein, Paul; McGrath, John J.; Hultman, Christina M.

doi:10.1001/jamapsychiatry.2013.1180

Cited by 147 publications

(52 citation statements)

References 46 publications

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“…More recently, studies have suggested that grandpaternal age (specifically on the mother’s line) may also contribute to the risk of neurodevelopmental disorders (23, 24). This may be understood when considering that phenotypes associated with predisposing mutations tend to be more pronounced in males than in females,, therefore effectively leading to the skipping of generations.…”

Section: Advanced Paternal Age and Mental Disordersmentioning

confidence: 99%

“Selfish Spermatogonial Selection”: A Novel Mechanism for the Association Between Advanced Paternal Age and Neurodevelopmental Disorders

Goriely

McGrath²,

Hultman³

et al. 2013

AJP

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Objectives There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders such as schizophrenia and autism. Here we present a novel mechanism that may contribute to this association. Methods Narrative review. Results Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy-errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation via dysregulation of the RAS pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare paternal age-effect disorders (e.g. Apert syndrome, achondroplasia), this process is known as ‘selfish spermatogonial selection’. This mechanism will (a) favor propagation of germ cells carrying pathogenic mutations, (b) increasingly skew the mutational profile of sperm as men age, and (c) result in an enrichment of de novo mutations in the offspring of older fathers that preferentially impact on specific cellular signaling pathways. This mechanism offers a parsimonious explanation not only for the association between advanced paternal age and various neurodevelopmental disorders, but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle) and some epidemiological features of these disorders. We outline hypotheses to test this model. Conclusions In light of our current understanding of the genetic networks involved in neurocognitive disorders and the principles of selfish spermatogonial selection, we speculate that some pathogenic mutations associated with these disorders are the consequence of a selfish mechanism originating in the aging testis. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications.

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Section: Advanced Paternal Age and Mental Disordersmentioning

confidence: 99%

“Selfish Spermatogonial Selection”: A Novel Mechanism for the Association Between Advanced Paternal Age and Neurodevelopmental Disorders

Goriely

McGrath²,

Hultman³

et al. 2013

AJP

Self Cite

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“…Changes in diagnostic criteria and increased attention by the medical community have certainly contributed to this trend [4]. Also, increasing parental age at conception has been shown to confer ASD risk [5], as well as some environmental factors, active especially during critical periods in prenatal/early postnatal neurodevelopment [6]. Finally, genetic susceptibility plays a prominent role in ASD pathogenesis through complex and heterogeneous underpinnings, ranging from rare variants endowed with full penetrance to common variants each explaining very small proportions of the overall phenotypic variance, either alone or through gene × environment interactions [7, 8].…”

Section: Introductionmentioning

confidence: 99%

Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

et al. 2016

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BackgroundAutism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of “control” status.MethodsASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2–7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway.ResultsUrinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate.ConclusionsThe metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0109-5) contains supplementary material, which is available to authorized users.

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“…However, the risk for most conditions is linearly associated with paternal aging, so the risks to offspring of fathers in who are in their 30's may be doubled in comparison to offspring with a father in his 20's. An autism study furthermore demonstrated that a paternal age related vulnerability may persist across generations, with age of grandfathers independently associated with the autism risk in their grandchildren[4]. …”

Section: Introductionmentioning

confidence: 99%

Paternal age and mental health of offspring

Malaspina

Gilman

Kranz

2015

Fertility and Sterility

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The influence of paternal age on the risk for sporadic forms of Mendelian disorders is well known, but a burgeoning recent literature also demonstrates a paternal age effect for complex neuropsychiatric conditions, including schizophrenia, autism, bipolar disorder and even for learning potential, expressed as intelligence. Mental illness is costly to the patients, the family and the public health system, accounting for the largest portion of disability costs in our economy. The delayed onset of neuropsychiatric conditions and lack of physical manifestations at birth are common frequencies in the population that have obscured the recognition that a portion of the risks for mental conditions is associated with paternal age. Identification of these risk pathways may be leveraged for knowledge about mental function and for future screening tests. However, only a small minority of at-risk offspring are likely to have such a psychiatric or learning disorder attributable to paternal age, including the children of older fathers.

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Autism Risk Across Generations

Cited by 147 publications

References 46 publications

“Selfish Spermatogonial Selection”: A Novel Mechanism for the Association Between Advanced Paternal Age and Neurodevelopmental Disorders

“Selfish Spermatogonial Selection”: A Novel Mechanism for the Association Between Advanced Paternal Age and Neurodevelopmental Disorders

Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

Paternal age and mental health of offspring

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