Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence
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- 作者：Beate St Pourcain (12) (13) (14)
David H Skuse (15)
William P Mandy (16)
Kai Wang (17) (18)
Hakon Hakonarson (17)
Nicholas J Timpson (12)
David M Evans (12) (19)
John P Kemp (12) (19)
Susan M Ring (12)
Wendy L McArdle (20)
Jean Golding (20) (21)
George Davey Smith (12) - 关键词：ALSPAC ; ASD ; Autism ; GCTA heritability ; GWAS ; Social communication
- 刊名：Molecular Autism
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：5
- 期：1
- 全文大小：709 KB
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David H Skuse (15)
William P Mandy (16)
Kai Wang (17) (18)
Hakon Hakonarson (17)
Nicholas J Timpson (12)
David M Evans (12) (19)
John P Kemp (12) (19)
Susan M Ring (12)
Wendy L McArdle (20)
Jean Golding (20) (21)
George Davey Smith (12)
12. The Medical Research Council Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
13. School of Oral and Dental Sciences, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY, UK
14. School of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol, BS8 1TU, UK
15. Behavioural Sciences Unit, Institute of Child Health, University College London, Gower Street, London, WC1E 6BT, UK
16. Research Department of Clinical, Educational and Health Psychology, University College London, Gower Street, London, WC1E 6BT, UK
17. Children’s Hospital of Philadelphia and Perelman School of Medicine, 3615 Civic Center Boulevard, Philadelphia, PA, 19104, USA
18. Zilkha Neurogenetic Institute & Department of Psychiatry, Keck School of Medicine of the University of Southern California, 1501 San Pablo St, Los Angeles, CA, 90089, USA
19. Translational Research Institute, University of Queensland Diamantina Institute, Level 7, 37 Kent St, Woolloongabba, QLD, 4102, Australia
20. School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
21. Centre for Child and Adolescent Health, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK - ISSN：2040-2392
文摘
Background Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence. Methods Social-communication difficulties were ascertained at ages 8, 11, 14 and 17?years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N?≤-,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P?≤-0?) were also followed up in Autism Genetic Resource Exchange pedigrees (N--93) and the Autism Case Control cohort (N cases/N controls--,204/6,491). Results GCTA heritability was strongest in childhood (h 2 (8 years)--.24) and especially in later adolescence (h 2 (17 years)--.45), with a marked drop during early to middle adolescence (h 2 (11 years)--.16 and h2 (14 years)--.08). Genome-wide screens at ages 8 and 17?years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P--.3?×-0?; genome-wide empirical P--.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P--.9?×-0?; genome-wide empirical P--.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical P co-location--.007). Conclusions Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum.