Polygenic Risk Scores for Developmental Disorders, Neuromotor Functioning During Infancy, and Autistic Traits in Childhood

doi:10.1016/j.biopsych.2019.06.006

Biological Psychiatry

Volume 87, Issue 2, 15 January 2020, Pages 132-138

https://doi.org/10.1016/j.biopsych.2019.06.006 Get rights and content

Abstract

Background

Impaired neuromotor development is often one of the earliest observations in children with autism spectrum disorder (ASD). We investigated whether a genetic predisposition to developmental disorders was associated with nonoptimal neuromotor development during infancy and examined the genetic correlation between nonoptimal neuromotor development and autistic traits in the general population.

Methods

In a population-based cohort in The Netherlands (2002–2006), we calculated polygenic risk scores (PRSs) for ASD and attention-deficit/hyperactivity disorder (ADHD) using genome-wide association study summary statistics. In 1921 children with genetic data, parents rated autistic traits at 6 years of age. Among them, 1174 children (61.1%) underwent neuromotor examinations (tone, responses, senses, and other observations) during infancy (9–20 weeks of age). We used linear regressions to examine associations of PRSs with neuromotor scores and autistic traits. We performed a bivariate genome-based restricted maximum likelihood analysis to explore whether genetic susceptibility underlies the association between neuromotor development and autistic traits.

Results

Higher PRSs for ASD were associated with less optimal overall infant neuromotor development, in particular low muscle tone. Higher PRSs for ADHD were associated with less optimal senses. PRSs for ASD and those for ADHD both were associated with autistic traits. The single nucleotide polymorphism–based heritability of overall motor development was 20% (SE = .21) and of autistic traits was 68% (SE = .26). The genetic correlation between overall motor development and autistic traits was .35 (SE = .21, p < .001).

Conclusions

We found that genetic liabilities for ASD and ADHD covary with neuromotor development during infancy. Shared genetic liability might partly explain the association between nonoptimal neuromotor development during infancy and autistic traits in childhood.

Section snippets

Methods and Materials

This study was embedded in the Generation R Study, a population-based birth cohort in Rotterdam, The Netherlands, which recruited more than 9000 pregnant women with a delivery date from April 2002 to January 2006 to study early determinants of development and health in childhood and adolescence (15). From this birth cohort, we included a pediatric sample of European ancestry with available genotype data (n = 2830) (16). Between 9 and 20 weeks of age, 1174 infants (41% of 2830 with genotyping

Results

Children had an average neuromotor score of 1.67 (SD = 0.96), mean age at neuromotor assessment was 12.6 weeks (SD = 20), and 48.7% of children were girls. Mothers were on average 31.3 years old (SD = 4.7), and 55% of them completed higher education.

A higher PRS_ASD was positively associated with less optimal overall neuromotor development during infancy (e.g., with GWAS p_T < 1, β = .048, 95% confidence interval [CI] = .007, .090, p = .02) (Figure 1 and Table 1). There was a relationship between

Discussion

In this population-based study of children from European ancestry, a higher genetic liability for ASD was associated with less optimal overall infant neuromotor development and low muscle tone at 9 to 20 weeks of age. Genetic susceptibility contributes to both less optimal infant neuromotor development and autistic traits at 6 years of age. Both ASD and ADHD genetic susceptibility were related to less optimal senses and other observations and autistic traits in boys only.

Previous studies have

Acknowledgments and Disclosures

The general design of the Generation R Study is supported by the Erasmus Medical Center Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw “Geestkracht” programme 10.000.1003), the Netherlands Organization for Scientific Research (NOW), and the Ministry of Health, Welfare and Sport. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and the Faculty of Social Sciences of

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Childhood cross-trait analyses were mostly limited to ADHD and ASD (Table S3, available online), with studies showing associations between PRSs of ADHD and ASD, and childhood conduct disorder symptoms, irritability, ADHD symptoms, social communication problems/autistic traits, eating disorder symptoms, anxiety and depression as well as higher symptom levels in latent externalizing, internalizing, and general psychopathology factors (Table 2).36,51-64 Further, female participants with clinical diagnoses of anxiety and depression were found to have higher ADHD PRSs than male participants,52 while male, but not female, participants with higher ADHD PRSs had higher autistic trait scores.56 As with the PRS analyses, childhood cross-trait analyses using GREML and LDSC generally focused on ADHD and ASD, with reported genetic correlations of up to 0.37 based on clinical samples (Figure 3, Table S4, available online).20,87,88
A systematic review of studies using molecular genetics and statistical approaches to investigate the role of common genetic variation in the development, persistence, and comorbidity of childhood psychiatric traits was conducted.
A literature review was performed using the PubMed database, following PRISMA guidelines. There were 131 studies meeting inclusion criteria, having investigated at least one type of childhood-onset or childhood-measured psychiatric disorder or trait with the aim of identifying trait-associated common genetic variants, estimating the contribution of single nucleotide polymorphisms (SNPs) to the amount of variance explained (SNP-based heritability), investigating genetic overlap between psychiatric traits, or investigating whether the stability in traits or the association with adult traits is explained by genetic factors.
The first robustly associated genetic variants have started to be identified for childhood psychiatric traits. There were substantial contributions of common genetic variants to many traits, with variation in single nucleotide polymorphism heritability estimates depending on age and raters. Moreover, genetic variants also appeared to explain comorbidity as well as stability across a range of psychiatric traits in childhood and across the life span.
Common genetic variation plays a substantial role in childhood psychiatric traits. Increased sample sizes will lead to increased power to identify genetic variants and to understand genetic architecture, which will ultimately be beneficial to targeted and prevention strategies. This can be achieved by harmonizing phenotype measurements, as is already proposed by large international consortia and by including the collection of genetic material in every study.
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Only one study (on autism) reported a significant positive association with the ADHD PRS, although full effect sizes were not provided.67 One study on autistic traits reported a significant positive association in male participants only but the effect was not present for the full sample or in female participants.64 All but 1 of the 8 studies on brain structure or connectivity29,49,54,56,63,65,66 reported significant associations with the ADHD PRS.
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Archival ReportPolygenic Risk Scores for Developmental Disorders, Neuromotor Functioning During Infancy, and Autistic Traits in Childhood

Abstract

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Results

Discussion

Acknowledgments and Disclosures

Lancet

Am J Hum Genet

Eur J Paediatr Neurol

Biol Psychiatry

NeuroImage

Neurosci Biobehav Rev

J Am Acad Child Adolesc Psychiatry

Biol Psychiatry

Autistic traits in the general population: A twin study

Arch Gen Psychiatry

Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis

Lancet

Evidence that autistic traits show the same etiology in the general population and at the quantitative extremes (5%, 2.5%, and 1%)

Arch Gen Psychiatry

The emergence of autism spectrum disorder: Insights gained from studies of brain and behaviour in high-risk infants

Curr Opin Psychiatry

Motor abnormalities: From neurodevelopmental to neurodegenerative through “functional” (neuro)psychiatric disorders

Schizophr Bull

Motor coordination in autism spectrum disorders: A synthesis and meta-analysis

J Autism Dev Disord

A prospective case series of high-risk infants who developed autism

J Autism Dev Disord

Movement analysis in infancy may be useful for early diagnosis of autism

Proc Natl Acad Sci U S A

Infant muscle tone and childhood autistic traits: A longitudinal study in the general population

Autism Res

Relation of infant motor development with nonverbal intelligence, language comprehension and neuropsychological functioning in childhood: A population-based study

Dev Sci

Inflexible neurobiological signatures precede atypical development in infants at high risk for autism

Sci Rep

Early brain development in infants at high risk for autism spectrum disorder

Nature

Attention and motor deficits index non-specific background liabilities that predict autism recurrence in siblings

J Neurodev Disord

The Generation R Study: Design and cohort update 2017

Eur J Epidemiol

Association of genetic risk for schizophrenia and bipolar disorder with infant neuromotor development

JAMA Psychiatry

Challenges in conducting genome-wide association studies in highly admixed multi-ethnic populations: The Generation R Study

Eur J Epidemiol

A linear complexity phasing method for thousands of genomes

Nat Methods

A flexible and accurate genotype imputation method for the next generation of genome-wide association studies

PLoS Genet

Archival Report
Polygenic Risk Scores for Developmental Disorders, Neuromotor Functioning During Infancy, and Autistic Traits in Childhood