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SA20COPY Number variants and polygenic risk scores in adults with autism spectrum disorder (ASD): results from the NCMH adult ASD cohort

Underwood, Jack, Kendall, Kimberley, Berrett, Jennifer, Anney, Richard, Bree, Marianne Van Den and Hall, Jeremy 2019. SA20COPY Number variants and polygenic risk scores in adults with autism spectrum disorder (ASD): results from the NCMH adult ASD cohort. European Neuropsychopharmacology 29 (S4) , S1198-S1199. 10.1016/j.euroneuro.2018.08.242

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Background: Autism Spectrum Disorders (ASD) are lifelong neurodevelopmental conditions characterised by persistent difficulties in reciprocal social interaction, communication, restricted interests, stereotypic behaviours and resistance to change. The increasing recognition of adult ASD has resulted in the ongoing development of specialist services, some of which offer genetic testing for individuals with ASD. This study aims to examine i) the rate of rare neurodevelopmental copy number variants (CNVs) and, ii) the polygenic risk scores (PRS) of a cohort of individuals diagnosed with ASD in adulthood. Methods: 90 individuals with ASD but without intellectual disability, and 60 age- and sex-matched controls were drawn from the National Centre for Mental Health (NCMH) sample. Inclusion criteria were diagnosis of ASD at age ≥18 consistent with ICD10 diagnostic criteria by secondary health care professional on casenote review, without comorbid intellectual disability. Clinical psychiatric, physical and social phenotypic data and DNA was retrieved. Genotyping was carried out on two versions of the Illumina PsychChip. CNVs were called from the 90% common content of the two chips using PennCNV run through a Galaxy pipeline. We then annotated a list of 53 CNVs associated with neurodevelopmental disorders. For PRS analysis, PRS scores for ASD, attention deficit hyperactivity disorder, bipolar affective disorder, major depressive disorder, Alzheimer's disease and schizophrenia were generated following marker and individual quality control. Results: The rate of neurodevelopmental CNVs was 3.8% (n = 5) in individuals with ASD and 1.3% (n = 1) in control but this difference was not statistically significant. The five neurodevelopmental CNVs detected were 2q13 deletion (n = 2), 15q13.3 duplication (n = 1), 16p13.11 duplication (n = 1) in individuals with ASD and a 2p16.3 deletion in a control individual. Of the PRS scores calculated by presence or absence of ASD, only the PRS derived from the ASD GWAS showed statistically significant difference by caseness. We calculate that approximately 0.1286 (P < .00001) of variance can be explained from PRS derived from linkage independent markers showing association at P < 1e-3 in the ASD GWAS (SNPS in model = 433). Discussion: Individuals with ASD had an increased rate of neurodevelopmental CNVs though this was not statistically significant. A statistically significant increase in burden of CNVs in this group might be confirmed in a larger sample. However, it appears that the CNV rate was lower than that reported in pediatric ASD populations, who may have a greater neurodevelopmental symptom profile. PRS analysis demonstrated a significant contribution of polygenic load of ASD-associated common variants, detectable even in this relatively small sample size. Taken together, these results suggest that adults presenting with ASD may have a lower burden of rare penetrant variants and a higher polygenic contribution of common risk alleles than childhood ASD populations, potentially reflecting less severe neurodevelopmental disability.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 0924-977X
Last Modified: 23 Feb 2021 12:30

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