Journal Article

CNVs conferring risk of autism or schizophrenia affect cognition in controls

Meyer-Lindenberg, Andreas, Haraldsson, Magnus, Stefansdottir, Berglind, Hreidarsson, Stefan, Bjornsdottir, Gyda, Jonsson, Gudbjorn F., Thygesen, Johan H., Steinberg, Stacy, Halldorsson, Jonas G., Kapur, Shitij, Morgen, Katrin, Snorrason, Heimir, Stefansson, Kari, Walters, G. Bragi, Tost, Heike, Didriksen, Michael, Schwarz, Adam J., Arnarsdottir, Sunna, Doyle, Orla M., Magnusdottir, Brynja, Kristjansdottir, Solveig, Stensbøl, Tine B., Jonsdottir, Birna, Saemundsen, Evald, Jonsdottir, Gudrun A., Brammer, Michael, Sigurdsson, Engilbert, Stefansson, Hreinn, Grimm, Oliver, Gudmundsson, Larus J., Davidsdottir, Solveig R., Helgadottir, Isafold

2014

Overview

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia. Rare copy-number variants (CNVs) conferring risk of schizophrenia or autism affect fecundity of carriers in Iceland, and carriers of these CNVs who do not suffer disease or have not been diagnosed with intellectual disability show phenotypes in brain structure and cognitive abilities between those of non-carrier controls and patients with schizophrenia. Genetic variation in autism and schizophrenia Certain rare copy-number variants (CNVs), in which sections of the genome are repeated, have previously been linked to schizophrenia and autism but their carriers do not always suffer either disease or obvious intellectual disability. Kari Stefansson and colleagues studied a group of Icelandic carriers of these variants and show that although disease-free, their brains are subtly different from those of controls that don't carry such mutations. The CNVs do not all affect the same cognitive domains but one in particular, the 15q11.2(BP1-BP2) deletion, affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia. By studying these carriers more closely it may prove possible to pinpoint more precisely which abnormalities put carriers at risk of developing schizophrenia.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/22 / 45/23 / 45/43 / 45/61 / 631/208/205/2138 / Adolescent / Adult / Aged / Autism / Autistic Disorder - genetics / Brain - abnormalities / Brain - anatomy & histology / Brain - metabolism / Case-Control Studies / Chromosome Deletion / Chromosomes, Human - genetics / Chromosomes, Human, Pair 15 - genetics / Cognition / Cognition & reasoning / Cognition - physiology / Cognitive ability / Copy number variations / Disease / DNA Copy Number Variations - genetics / Dyslexia / Dyslexia - genetics / Fecundity / Female / Fertility - genetics / Genetic aspects / Genetic Predisposition to Disease / Heterozygote / Humanities and Social Sciences / Humans / Iceland / Learning Disabilities - genetics / Magnetic Resonance Imaging / Male / Memory / Mental disorders / Middle Aged / multidisciplinary / Neuropsychological Tests / Phenotype / Physiological aspects / Population / Schizophrenia / Schizophrenia - genetics / Science / Young Adult