Advancing paternal age and simplex autism

Puleo, Connor M.; Schmeidler, James; Reichenberg, Abraham; Kolevzon, Alexander; Soorya, Latha; Buxbaum, Joseph D.; Silverman, Jeremy M.

doi:10.1177/1362361311427154

Cited by 32 publications

(20 citation statements)

References 33 publications

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“…The sex-specific neuroanatomy discovered here for high-functioning adults with autism are in line with the growing evidence of sex-specific biological profiles for the high-functioning subgroup at the levels of serum proteomics (Schwarz et al , 2011; Ramsey et al , 2012), sex steroid hormones and anthropometry (Ruta et al , 2011; Bejerot et al , 2012), and for the whole autism spectrum at the levels of genetics (Gilman et al , 2011; Puleo et al , 2012; Szatmari et al , 2012), transcriptomics (Kong et al , 2012) and early brain overgrowth (Sparks et al , 2002; Bloss and Courchesne, 2007; Schumann et al , 2009, 2010; Nordahl et al , 2011). In sum, high-functioning males and females with autism, though diagnosed by the same behavioural criteria, differ in aspects of neuroanatomy.…”

Section: Discussionsupporting

confidence: 84%

“…Although some studies report no sex differences in cardinal autistic behavioural characteristics after controlling for IQ (Tsai and Beisler, 1983; Pilowsky et al , 1998; Holtmann et al , 2007; Solomon et al , 2012), others do (McLennan et al , 1993; Carter et al , 2007; Hartley and Sikora, 2009; Lai et al , 2011; Mandy et al , 2012). Females with autism have also been found to differ from males with autism at the levels of cognition (Carter et al , 2007; Bolte et al , 2011; Lemon et al , 2011; Lai et al , 2012 b ), proteomics (Schwarz et al , 2011; Ramsey et al , 2012), hormones (Ruta et al , 2011; Bejerot et al , 2012), genetics (Gilman et al , 2011; Puleo et al , 2012; Szatmari et al , 2012), transcriptomics (Kong et al , 2012), and early brain overgrowth (Sparks et al , 2002; Bloss and Courchesne, 2007; Schumann et al , 2009, 2010; Nordahl et al , 2011). Structural neuroimaging studies focusing on females (Craig et al , 2007; Calderoni et al , 2012) also reveal little overlap of atypical brain areas compared with those found in meta-analyses of predominantly male samples (Radua et al , 2011; Via et al , 2011).…”

Section: Introductionmentioning

confidence: 99%

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Biological sex affects the neurobiology of autism

Lai

Lombardo

Suckling

et al. 2013

Brain

249

266

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In autism, heterogeneity is the rule rather than the exception. One obvious source of heterogeneity is biological sex. Since autism was first recognized, males with autism have disproportionately skewed research. Females with autism have thus been relatively overlooked, and have generally been assumed to have the same underlying neurobiology as males with autism. Growing evidence, however, suggests that this is an oversimplification that risks obscuring the biological base of autism. This study seeks to answer two questions about how autism is modulated by biological sex at the level of the brain: (i) is the neuroanatomy of autism different in males and females? and (ii) does the neuroanatomy of autism fit predictions from the ‘extreme male brain’ theory of autism, in males and/or in females? Neuroanatomical features derived from voxel-based morphometry were compared in a sample of equal-sized high-functioning male and female adults with and without autism (n = 120, n = 30/group). The first question was investigated using a 2 × 2 factorial design, and by spatial overlap analyses of the neuroanatomy of autism in males and females. The second question was tested through spatial overlap analyses of specific patterns predicted by the extreme male brain theory. We found that the neuroanatomy of autism differed between adult males and females, evidenced by minimal spatial overlap (not different from that occurred under random condition) in both grey and white matter, and substantially large white matter regions showing significant sex × diagnosis interactions in the 2 × 2 factorial design. These suggest that autism manifests differently by biological sex. Furthermore, atypical brain areas in females with autism substantially and non-randomly (P < 0.001) overlapped with areas that were sexually dimorphic in neurotypical controls, in both grey and white matter, suggesting neural ‘masculinization’. This was not seen in males with autism. How differences in neuroanatomy relate to the similarities in cognition between males and females with autism remains to be understood. Future research should stratify by biological sex to reduce heterogeneity and to provide greater insight into the neurobiology of autism.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Biological sex affects the neurobiology of autism

Lai

Lombardo

Suckling

et al. 2013

Brain

249

266

View full text Add to dashboard Cite

show abstract

“…This raises the possibility that higher maternal age is a greater risk factor for male than female offspring. Intriguingly, a converse pattern has been observed for paternal age, with paternal age appearing to pose the greatest risk for female offspring (Croen et al, 2007;Reichenberg et al, 2006), in particular simplex autism (Puleo et al, 2012). However, a recent large-scale study failed to find sexmoderating effect on risks for offspring ASC associated with increased parental ages (Sandin et al, 2015).…”

Section: Maternal Agementioning

confidence: 99%

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition

Mandy

Lai

2016

Child Psychology Psychiatry

216

142

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Future investigations should consider the specificity of risks for ASC versus other atypical neurodevelopmental trajectories, timing of risk and protective mechanisms, animal model systems to study mechanisms underlying gene-environment interplay, large-sample genome-envirome designs to address G × E and longitudinal studies to elucidate how rGE plays out over time. Clinical and public health implications are discussed.

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“…Despite evidence for a likely involvement of de novo and environmental or epigenetic risk factors, including maternal antibodies 16 or stress during pregnancy 17 and paternal age, 18,19 we contend that coding variations contribute substantially to the heritability of ASD and can be successfully detected and assembled into connected pathways with GWAS—if the experimental design, the primary outcome, the statistical methods used, and the decision rules applied were better targeted toward the particulars of non-randomized studies of common diseases. With u -statistics for genetically structured wide-locus data comprising several neighboring SNPs (μGWAS) addressing the former two conditions, we have recently confirmed axonal guidance and Ca 2+ signaling as key pathways in childhood absence epilepsy (CAE) 20 from 185 cases and publicly available controls only.…”

Section: Introductionmentioning

confidence: 96%

A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism

Sonakya

Bigio

et al. 2014

Transl Psychiatry

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The prevalence of autism spectrum disorders (ASDs) has increased 20-fold over the past 50 years to >1% of US children. Although twin studies attest to a high degree of heritability, the genetic risk factors are still poorly understood. We analyzed data from two independent populations using u-statistics for genetically structured wide-locus data and added data from unrelated controls to explore epistasis. To account for systematic, but disease-unrelated differences in (non-randomized) genome-wide association studies (GWAS), a correlation between P-values and minor allele frequency with low granularity data and for conducting multiple tests in overlapping genetic regions, we present a novel study-specific criterion for ‘genome-wide significance'. From recent results in a comorbid disease, childhood absence epilepsy, we had hypothesized that axonal guidance and calcium signaling are involved in autism as well. Enrichment of the results in both studies with related genes confirms this hypothesis. Additional ASD-specific variations identified in this study suggest protracted growth factor signaling as causing more severe forms of ASD. Another cluster of related genes suggests chloride and potassium ion channels as additional ASD-specific drug targets. The involvement of growth factors suggests the time of accelerated neuronal growth and pruning at 9–24 months of age as the period during which treatment with ion channel modulators would be most effective in preventing progression to more severe forms of autism. By extension, the same computational biostatistics approach could yield profound insights into the etiology of many common diseases from the genetic data collected over the last decade.

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Advancing paternal age and simplex autism

Cited by 32 publications

References 33 publications

Biological sex affects the neurobiology of autism

Biological sex affects the neurobiology of autism

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition

A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism

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