title: Discontinuity in the genetic and environmental causes of the intellectual disability spectrum.
abstract: Intellectual disability (ID) occurs in almost 3% of newborns. Despite substantial research, a fundamental question about its origin and links to intelligence (IQ) still remains. ID has been shown to be inherited and has been accepted as the extreme low of the normal IQ distribution. However, ID displays a complex pattern of inheritance. Previously, noninherited rare mutations were shown to contribute to severe ID risk in individual families, but in the majority of cases causes remain unknown. Common variants associated with ID risk in the population have not been systematically established. Here we evaluate the hypothesis, originally proposed almost 1 century ago, that most ID is caused by the same genetic and environmental influences responsible for the normal distribution of IQ, but that severe ID is not. We studied more than 1,000,000 sibling pairs and 9,000 twin pairs assessed for IQ and for the presence of ID. We evaluated whether genetic and environmental influences at the extremes of the distribution are different from those operating in the normal range. Here we show that factors influencing mild ID (lowest 3% of IQ distribution) were similar to those influencing IQ in the normal range. In contrast, the factors influencing severe ID (lowest 0.5% of IQ distribution) differ from those influencing mild ID or IQ scores in the normal range. Taken together, our results suggest that most severe ID is a distinct condition, qualitatively different from the preponderance of ID, which, in turn, represents the low extreme of the normal distribution of intelligence.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; avi.reichenberg@mssm.edu.
authors.forename: Abraham
authors.initials: A
authors.lastname: Reichenberg
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Martin
authors.initials: M
authors.lastname: Cederlöf
authors.affiliation: Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, SE5 8AF London, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: McMillan
authors.affiliation: Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, SE5 8AF London, United Kingdom;
authors.forename: Maciej
authors.initials: M
authors.lastname: Trzaskowski
authors.affiliation: Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, 52621 Ramat Gan, Israel;
authors.forename: Ori
authors.initials: O
authors.lastname: Kapra
authors.affiliation: Department of Mental Health, Israel Medical Corps, 01259 Tel-Hashomer, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Fruchter
authors.affiliation: Department of Mental Health, Israel Medical Corps, 01259 Tel-Hashomer, Israel.
authors.forename: Karen
authors.initials: K
authors.lastname: Ginat
authors.affiliation: Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, 52621 Ramat Gan, Israel;
authors.forename: Michael
authors.initials: M
authors.lastname: Davidson
authors.affiliation: Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, 52621 Ramat Gan, Israel; Department of Mental Health, Israel Medical Corps, 01259 Tel-Hashomer, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Weiser
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Henrik
authors.initials: H
authors.lastname: Larsson
authors.affiliation: Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, SE5 8AF London, United Kingdom;
authors.forename: Robert
authors.initials: R
authors.lastname: Plomin
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Paul
authors.initials: P
authors.lastname: Lichtenstein
mesh_terms: D000293:Adolescent; D004777:Environment; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology* / Q000235:genetics; D007360:Intelligence; D008297:Male; D014427:Twins / Q000235:genetics
keywords: family study; heritability; intellectual disability; intelligence; twins