Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
30258228
TITLE
Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.
ABSTRACT
. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.
DATE PUBLISHED
2018 Sep 26
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2018/05/04
accepted 2018/09/04
entrez 2018/09/28 06:00
pubmed 2018/09/28 06:00
medline 2018/09/28 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Niemi MEK Niemi Mari E K MEK Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Martin HC Martin Hilary C HC Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Rice DL Rice Daniel L DL Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Gallone G Gallone Giuseppe G Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Gordon S Gordon Scott S QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Kelemen M Kelemen Martin M Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
McAloney K McAloney Kerrie K QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
McRae J McRae Jeremy J Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Radford EJ Radford Elizabeth J EJ Department of Paediatrics, University of Cambridge, Cambridge, UK.
Yu S Yu Sui S Department of Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, Adelaide, South Australia, Australia.
Gecz J Gecz Jozef J South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Wright CF Wright Caroline F CF University of Exeter Medical School, Institute of Biomedical and Clinical Science, RILD, Royal Devon & Exeter Hospital, Exeter, UK.
Fitzpatrick DR Fitzpatrick David R DR MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Firth HV Firth Helen V HV Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Hurles ME Hurles Matthew E ME Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Barrett JC Barrett Jeffrey C JC Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. jeff.barrett@genomicsplc.com.
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2018
MONTH: Sep
DAY: 26
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-4687
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
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