Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Autism
Published in: Molecular Autism 1/2014

Open Access 01-12-2014 | Research

Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence

Authors: Beate St Pourcain, David H Skuse, William P Mandy, Kai Wang, Hakon Hakonarson, Nicholas J Timpson, David M Evans, John P Kemp, Susan M Ring, Wendy L McArdle, Jean Golding, George Davey Smith

Published in: Molecular Autism | Issue 1/2014

Login to get access

Abstract

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 ≤ 5,628) 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 ≤ 10−5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491).

Results

GCTA heritability was strongest in childhood (h2(8 years) = 0.24) and especially in later adolescence (h2(17 years) = 0.45), with a marked drop during early to middle adolescence (h2(11 years) = 0.16 and h2(14 years) = 0.08). 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 = 9.3 × 10−9; genome-wide empirical P = 0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P = 7.9 × 10−8; genome-wide empirical P = 0.085). 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 Pco-location = 0.007).

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.
Appendix
Available only for authorised users
Literature
1.
Wing L: The continuum of autistic characteristics. Diagnosis and Assessment in Autism. Edited by: Schopler E, Mesibov G. 1988, New York: Plenum, 91-110.CrossRef
2.
Mandy WPL, Skuse DH: Research review: What is the association between the social-communication element of autism and repetitive interests, behaviours and activities?. J Child Psychol Psychiatry. 2008, 49: 795-808. 10.1111/j.1469-7610.2008.01911.x.CrossRefPubMed
3.
American Psychiatric Association: Diagnostic and statistical manual of mental disorders. 2013, Arlington, VA: American Psychiatric Publishing, 5
4.
Piven J, Palmer P, Jacobi D, Childress D, Arndt S: Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Am J Psychiatry. 1997, 154: 185-190.CrossRefPubMed
5.
Constantino JN, Todd RD: Autistic traits in the general population: a twin study. Arch Gen Psychiatry. 2003, 60: 524-530. 10.1001/archpsyc.60.5.524.CrossRefPubMed
6.
Posserud MB, Lundervold AJ, Gillberg C: Autistic features in a total population of 7–9-year-old children assessed by the ASSQ (Autism Spectrum Screening Questionnaire). J Child Psychol Psychiatry. 2006, 47: 167-175. 10.1111/j.1469-7610.2005.01462.x.CrossRefPubMed
7.
Ronald A, Hoekstra RA: Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet. 2011, 156B: 255-274.CrossRefPubMed
8.
Lundström S, Chang Z, Råstam M, Gillberg C, Larsson H, Anckarsäter H, Lichtenstein P: Autism spectrum disorders and autistic like traits: similar etiology in the extreme end and the normal variation. Arch Gen Psychiatry. 2012, 69: 46-52. 10.1001/archgenpsychiatry.2011.144.CrossRefPubMed
9.
Robinson EB, Koenen KC, McCormick MC, Munir K, Hallett V, Happé F, Plomin R, Ronald A: 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. 2011, 68: 1113-1121. 10.1001/archgenpsychiatry.2011.119.PubMedCentralCrossRefPubMed
10.
St Pourcain B, Wang K, Glessner JT, Golding J, Steer C, Ring SM, Skuse DH, Grant SFA, Hakonarson H, Davey Smith G: Association between a high-risk autism locus on 5p14 and social-communication-spectrum phenotypes in the general population. Am J Psychiatry. 2010, 167: 1364-1372. 10.1176/appi.ajp.2010.09121789.PubMedCentralCrossRefPubMed
11.
12.
Chakrabarti B, Dudbridge F, Kent L, Wheelwright S, Hill-Cawthorne G, Allison C, Banerjee-Basu S, Baron-Cohen S: Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Autism Res. 2009, 2: 157-177. 10.1002/aur.80.CrossRefPubMed
13.
Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A: Individual common variants exert weak effects on risk for autism spectrum disorders. Hum Mol Genet. 2012, 21: 4781-4792. 10.1093/hmg/dds301.PubMedCentralCrossRefPubMed
14.
Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PMA, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A: Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009, 459: 528-533. 10.1038/nature07999.PubMedCentralCrossRefPubMed
15.
Weiss LA, Arking DE, Daly MJ, Chakravarti A: A genome-wide linkage and association scan reveals novel loci for autism. Nature. 2009, 461: 802-808. 10.1038/nature08490.PubMedCentralCrossRefPubMed
16.
Ronald A, Butcher LM, Docherty S, Davis OSP, Schalkwyk LC, Craig IW, Plomin R: A genome-wide association study of social and non-social autistic-like traits in the general population using pooled DNA, 500 K SNP microarrays and both community and diagnosed autism replication samples. Behav Genet. 2010, 40: 31-45. 10.1007/s10519-009-9308-6.PubMedCentralCrossRefPubMed
17.
St Pourcain B, Whitehouse AJO, Ang WQ, Warrington NM, Glessner JT, Wang K, Timpson NJ, Evans DM, Kemp JP, Ring SM, McArdle WL, Golding J, Hakonarson H, Pennell CE, Smith GD: Common variation contributes to the genetic architecture of social communication traits. Mol Autism. 2013, 4: 34-10.1186/2040-2392-4-34.PubMedCentralCrossRefPubMed
18.
19.
Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BHY, Cochrane L, Corsello C: Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010, 466: 368-372. 10.1038/nature09146.PubMedCentralCrossRefPubMed
20.
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC: Strong association of de novo copy number mutations with autism. Science. 2007, 316: 445-449. 10.1126/science.1138659.PubMedCentralCrossRefPubMed
21.
22.
Hobbs HH, Brown MS, Goldstein JL: Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992, 1: 445-466. 10.1002/humu.1380010602.CrossRefPubMed
23.
Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008, 40: 189-197. 10.1038/ng.75.PubMedCentralCrossRefPubMed
24.
Haworth C, Wright M, Luciano M, Martin N, de Geus E, van Beijsterveldt C, Bartels M, Posthuma D, Boomsma D, Davis O, Kovas Y, Corley R, DeFries J, Hewitt J, Olson R, Rhea SA, Wadsworth S, Iacono W, McGue M, Thompson L, Hart S, Petrill S, Lubinski D, Plomin R: The heritability of general cognitive ability increases linearly from childhood to young adulthood. Mol Psychiatry. 2010, 15: 1112-1120. 10.1038/mp.2009.55.PubMedCentralCrossRefPubMed
25.
St Pourcain B, Mandy WP, Heron J, Golding J, Davey Smith G, Skuse DH: Links between co-occurring social-communication and hyperactive-inattentive trait trajectories. J Am Acad Child Adolesc Psychiatry. 2011, 50: 892-902. 10.1016/j.jaac.2011.05.015.PubMedCentralCrossRefPubMed
26.
Hayiou-Thomas ME, Dale PS, Plomin R: The etiology of variation in language skills changes with development: a longitudinal twin study of language from 2 to 12 years. Dev Sci. 2012, 15: 233-249. 10.1111/j.1467-7687.2011.01119.x.CrossRefPubMed
27.
Skuse D, Mandy W, Steer C, Miller L, Goodman R, Lawrence K, Emond A, Golding J: Social communication competence and functional adaptation in a general population of children: preliminary evidence for sex-by-verbal IQ differential risk. J Am Acad Child Adolesc Psychiatry. 2008, 48: 128-137.CrossRef
28.
Boyd A, Golding J, Macleod J, Lawlor DA, Fraser A, Henderson J, Molloy L, Ness A, Ring S, Davey Smith G: Cohort profile: the “Children of the 90s”—the index offspring of the Avon Longitudinal Study of Parents and Children. Int J Epidemiol. 2013, 42: 111-127. 10.1093/ije/dys064.PubMedCentralCrossRefPubMed
29.
Skuse D, Mandy W, Scourfield J: Measuring autistic traits: heritability, reliability and validity of the Social and Communication Disorders Checklist. Br J Psychiatry. 2005, 187: 568-572. 10.1192/bjp.187.6.568.CrossRefPubMed
30.
Paternoster L, Zhurov AI, Toma AM, Kemp JP, St Pourcain B, Timpson NJ, McMahon G, McArdle W, Ring SM, Smith GD, Richmond S, Evans DM: Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position. Am J Hum Genet. 2012, 90: 478-485. 10.1016/j.ajhg.2011.12.021.PubMedCentralCrossRefPubMed
31.
Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR: MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol. 2010, 34: 816-834. 10.1002/gepi.20533.PubMedCentralCrossRefPubMed
32.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006, 38: 904-909. 10.1038/ng1847.CrossRefPubMed
33.
Yang J, Manolio TA, Pasquale LR, Boerwinkle E, Caporaso N, Cunningham JM, de Andrade M, Feenstra B, Feingold E, Hayes MG, Hill WG, Landi MT, Alonso A, Lettre G, Lin P, Ling H, Lowe W, Mathias RA, Melbye M, Pugh E, Cornelis MC, Weir BS, Goddard ME, Visscher PM: Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet. 2011, 43: 519-525. 10.1038/ng.823.PubMedCentralCrossRefPubMed
34.
Lee SH, Yang J, Goddard ME, Visscher PM, Wray NR: Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. Bioinformatics. 2012, 28: 2540-2542. 10.1093/bioinformatics/bts474.PubMedCentralCrossRefPubMed
35.
Faraway JJ: Extending the Linear Model with R: Generalized Linear, Mixed Effects and Nonparametric Regression Models. 2006, Boca Raton, FL: Chapman & Hall/CRC Press
36.
Moskvina V, Craddock N, Holmans P, Nikolov I, Pahwa JS, Green E, Owen MJ, O’Donovan MC: Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatry. 2008, 14: 252-260.PubMedCentralCrossRefPubMed
37.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007, 81: 559-575. 10.1086/519795.PubMedCentralCrossRefPubMed
38.
Moskvina V, Schmidt KM, Vedernikov A, Owen MJ, Craddock N, Holmans P, O’Donovan MC: Permutation-based approaches do not adequately allow for linkage disequilibrium in gene-wide multi-locus association analysis. Eur J Hum Genet. 2012, 20: 890-896. 10.1038/ejhg.2012.8.PubMedCentralCrossRefPubMed
39.
Gelman A, Hill J: Data Analysis Using Regression and Multilevel/Hierarchical Models. 2007, New York: Cambridge University Press
40.
Lord C, Rutter M, Le Couteur A: Autism Diagnostic Interview–Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994, 24: 659-685. 10.1007/BF02172145.CrossRefPubMed
41.
Lange C, Laird NM: On a general class of conditional tests for family-based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations. Genet Epidemiol. 2002, 23: 165-180. 10.1002/gepi.209.CrossRefPubMed
42.
Lord C, Risi S, Lambrecht L, Cook E, Leventhal BL, DiLavore PC, Pickles A, Rutter M: The Autism Diagnostic Observation Schedule–Generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000, 30: 205-223. 10.1023/A:1005592401947.CrossRefPubMed
43.
Marchini J, Howie B, Myers S, McVean G, Donnelly P: A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet. 2007, 39: 906-913. 10.1038/ng2088.CrossRefPubMed
44.
O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, MacKenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE: Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011, 43: 585-589. 10.1038/ng.835. A published erratum appears in Nat Genet 2012, 44:471PubMedCentralCrossRefPubMed
45.
Christian SL, Brune CW, Sudi J, Kumar RA, Liu S, Karamohamed S, Badner JA, Matsui S, Conroy J, McQuaid D, Gergel J, Hatchwell E, Gilliam TC, Gershon ES, Nowak NJ, Dobyns WB, Cook EH: Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry. 2008, 63: 1111-1117. 10.1016/j.biopsych.2008.01.009.PubMedCentralCrossRefPubMed
46.
Girirajan S, Dennis MY, Baker C, Malig M, Coe BP, Campbell CD, Mark K, Vu TH, Alkan C, Cheng Z, Biesecker LG, Bernier R, Eichler EE: Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet. 2013, 92: 221-237. 10.1016/j.ajhg.2012.12.016.PubMedCentralCrossRefPubMed
47.
Trzaskowski M, Dale PS, Plomin R: No genetic influence for childhood behavior problems from DNA analysis. J Am Acad Child Adolesc Psychiatry. 2013, 52: 1048-1056. 10.1016/j.jaac.2013.07.016.PubMedCentralCrossRefPubMed
48.
Wray NR, Yang J, Hayes BJ, Price AL, Goddard ME, Visscher PM: Pitfalls of predicting complex traits from SNPs. Nat Rev Genet. 2013, 14: 507-515. 10.1038/nrg3457.PubMedCentralCrossRefPubMed
49.
Plomin R, DeFries JC, Knopik VS, Neiderhiser JM: Behavioral Genetics. 2013, New York: Worth, 6
50.
Trzaskowski M, Yang J, Visscher PM, Plomin R: DNA evidence for strong genetic stability and increasing heritability of intelligence from age 7 to 12. Mol Psychiatry. in press. doi:10.1038/mp.2012.191
51.
Peterson AC, Taylor B: The biological approach to adolescence. Handbook of Adolescent Psychology. Edited by: Adelson J. 1980, New York: Wiley
52.
Montemayor R: Parents and adolescents in conflict: all families some of the time and some families most of the time. J Early Adolescence. 1983, 3: 83-103.CrossRef
53.
Blum R, Kafitz KW, Konnerth A: Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. Nature. 2002, 419: 687-693. 10.1038/nature01085.CrossRefPubMed
54.
Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M, Reichert J, Buxbaum JD, Meisler MH, The AGRE Consortium: Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Mol Psychiatry. 2003, 8: 186-194. 10.1038/sj.mp.4001241.CrossRefPubMed
55.
Kurian MA, Meyer E, Vassallo G, Morgan NV, Prakash N, Pasha S, Hai NA, Shuib S, Rahman F, Wassmer E, Cross JH, O’Callaghan FJ, Osborne JP, Scheffer IE, Gissen P, Maher ER: Phospholipase Cβ1 deficiency is associated with early-onset epileptic encephalopathy. Brain. 2010, 133: 2964-2970. 10.1093/brain/awq238.CrossRefPubMed
56.
Lo Vasco VR, Cardinale G, Polonia P: Deletion of PLCB1 gene in schizophrenia affected patients. J Cell Mol Med. 2012, 16: 844-851. 10.1111/j.1582-4934.2011.01363.x.CrossRefPubMed
Metadata
Title
Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence
Authors
Beate St Pourcain
David H Skuse
William P Mandy
Kai Wang
Hakon Hakonarson
Nicholas J Timpson
David M Evans
John P Kemp
Susan M Ring
Wendy L McArdle
Jean Golding
George Davey Smith
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2014
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/2040-2392-5-18

Other articles of this Issue 1/2014

Molecular Autism 1/2014 Go to the issue

Research

Behavioral signatures related to genetic disorders in autism

Research

Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards

Research

A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome

Research

Uncovering steroidopathy in women with autism: a latent class analysis

Research

Is inhibitory control a ‘no-go’ in adolescents with autism spectrum disorder?

Research

Single nucleotide polymorphism rs6716901 in SLC25A12 gene is associated with Asperger syndrome