Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population

T-K Clarke*, M. K. Lupton, A. M. Fernandez-Pujals, J. Starr, G. Davies, S. Cox, A. Pattie, D. C. Liewald, L. S. Hall, D. J. MacIntyre, B. H. Smith, L. J. Hocking, S. Padmanabhan, P. A. Thomson, C. Hayward, N. K. Hansell, G. W. Montgomery, S. E. Medland, N. G. Martin, M. J. WrightD. J. Porteous, I. J. Deary, A. M. McIntosh

*Corresponding author for this work

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Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (MD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta = 0.07, P=6 x 10(-7), r(2)= 0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta= 0.07, P=0.03, r(2\) = 0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta = - 0.08, Z =- 3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.

Original languageEnglish
Pages (from-to)419-425
Number of pages7
JournalMolecular Psychiatry
Issue number3
Early online date10 Mar 2015
Publication statusPublished - Mar 2016

Bibliographical note

Generation Scotland has received core funding from the Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 and the Scottish Funding Council HR03006. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants and nurses. We acknowledge with gratitude the financial support received for this work from the Dr Mortimer and Theresa Sackler Foundation. For the Lothian Birth Cohorts (LBC1921 and LBC1936), we thank Paul Redmond for database management assistance; Alan Gow, Martha Whiteman, Alison Pattie, Michelle Taylor, Janie Corley, Caroline Brett and Caroline Cameron for data collection and data entry; nurses and staff at the Wellcome Trust Clinical Research Facility, where blood extraction and genotyping was performed; staff at the Lothian Health Board; and the staff at the SCRE Centre, University of Glasgow. The research was supported by a program grant from Age UK (Disconnected Mind) and by grants from the Biotechnology and Biological Sciences Research Council (BBSRC). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Medical Research Council (MRC) and BBSRC is gratefully acknowledged. DJM is an NRS Career Research Fellow funded by the CSO. BATS were funded by the Australian Research Council (A79600334, A79906588, A79801419, DP0212016, DP0664638, and DP1093900) and the National Health and Medical Research Council (389875) Australia. MKL is supported by a Perpetual Foundation Wilson Fellowship. SEM is supported by a Future Fellowship (FT110100548) from the Australian Research Council. GWM is supported by a National Health and Medical Research Council (NHMRC), Australia, Fellowship (619667). We thank the twins and siblings for their participation, Marlene Grace, Ann Eldridge and Natalie Garden for cognitive assessments, Kerrie McAloney, Daniel Park, David Smyth and Harry Beeby for research support, Anjali Henders and staff in the Molecular Epidemiology Laboratory for DNA sample processing and preparation and Scott Gordon for quality control and management of the genotypes. This work is supported by a Stragetic Award from the Wellcome Trust, reference 104036/Z/14/Z.


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