Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence
Year: 2016
Type: article
Study design: Observational Study
Abstract: The chromosome bands 15q24.1-15q24.3 contain a complex region with numerous segmental duplications that predispose to regional microduplications and microdeletions, both of which have been linked to intellectual disability, speech delay and autistic features. The region may also harbour common inversion polymorphisms whose functional and phenotypic manifestations are unknown. Using single nucleotide polymorphism (SNP) data, we detected four large contiguous haplotype-genotypes at 15q24 with Mendelian inheritance in 2,562 trios, African origin, high population stratification and reduced recombination rates. Although the haplotype-genotypes have been most likely generated by decreased or absent recombination among them, we could not confirm that they were the product of inversion polymorphisms in the region. One of the blocks was composed of three haplotype-genotypes (N1a, N1b and N2), which significantly correlated with intelligence quotient (IQ) in 2,735 children of European ancestry from three independent population cohorts. Homozygosity for N2 was associated with lower verbal IQ (2.4-point loss, p-value = 0.01), while homozygosity for N1b was associated with 3.2-point loss in non-verbal IQ (p-value = 0.0006). The three alleles strongly correlated with expression levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for N2 correlated with over-expression of MAN2C1 over many brain areas but the occipital cortex where N1b homozygous highly under-expressed. Our population-based analyses suggest that MAN2C1 may contribute to the verbal difficulties observed in microduplications and to the intellectual disability of microdeletion syndromes, whose characteristic dosage increment and removal may affect different brain areas.
Source: PLoS ONE
Authors: Alejandro Cáceres, Tõnu Esko, Irene Pappa, Armand Gutiérrez, Maria-Jose Lopez-Espinosa, Sabrina Llop, Mariona Bustamante, Henning Tiemeier, Andres Metspalu, Peter K. Joshi, James F. Wilsonx, Judith Reina-Castillón, Jean Shin, Zdenka Pausova, Tomáš Paus, Jordi Sunyer, Luis A. Pérez-Jurado, Juan R. González
Institutions: Universitat Pompeu Fabra, Center for Research in Environmental Epidemiology, Barcelona Institute for Global Health, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Broad Institute, Boston Children's Hospital, Harvard University, University of Tartu, Erasmus MC, Erasmus University Rotterdam, Centre for Biomedical Network Research on Rare Diseases, Municipal Institute for Medical Research, Hospital del Mar Research Institute, Universitat Jaume I, Universitat de València, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, Centre for Genomic Regulation, Erasmus MC - Sophia Children’s Hospital, University of Edinburgh, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Toronto, Hospital for Sick Children, Rotman Research Institute, Universitat Autònoma de Barcelona
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: Heart and Stroke Foundation of Canada, Scottish Government, Royal Society, European Commission, ZonMw, Erasmus Universiteit Rotterdam, Eesti Teadusagentuur, Generalitat de Catalunya, Generalitat Valenciana, Institució Catalana de Recerca i Estudis Avançats, Ministerio de Ciencia e Innovación, Tartu Ülikool, Heart And Stroke Foundation Of Quebec, Canadian Institutes of Health Research, Medical Research Council, Instituto de Salud Carlos III, Center of Translational Genomics, University of Tartu, European Regional Development Fund, Conselleria de Sanitat Universal i Salut Pública
Awards: G1117880868, G1251492779, G1348827192, G1356384475, G1398108636, G1416398381, G1493030642, G1557994519, G1575554462, G1638066651, G1682873984, G1689944598, G1730050019, G1773966049, G1810489903, G1892331650, G216622859, G2189082656, G2206155153, G2347312180, G2531337759, G2712492024, G2867885658, G3001543491, G3042251962, G3158803353, G3221119883, G3227761751, G3266170463, G3297116590, G3427388544, G3559709381, G3588481721, G3624152618, G3624472861, G3630669391, G3662005835, G4131612797, G4153202515, G4296247274, G4419080526, G4442566642, European Network for Genetic and Genomic Epidemiology, G4757997566, G4823177629, G5000828053, G5114009594, G5153978940, G5185833053, G523383772, G5324658026, G5448335027, G5728381807, G5803789911, G582682078, G6033091583, Developmental neurotoxicity assessment of mixtures in children, G6650990183, G674505658, The mechanisms of immune tolerance, G7007108502, G7078175890, G740284655, G7426531139, G779508589, G7888910285, G7919137259, G8488632732, G8636635832, G9000232620, G970400076
OpenAlex ID: W2470501474