title: Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence.
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.
authors.affiliation: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Cáceres
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.|Broad Institute, Cambridge, Massachusetts, United States of America.|Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, United States of America.|Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands.|Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Pappa
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
authors.forename: Armand
authors.initials: A
authors.lastname: Gutiérrez
authors.affiliation: Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
authors.forename: Maria-Jose
authors.initials: MJ
authors.lastname: Lopez-Espinosa
authors.affiliation: Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Llop
authors.affiliation: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Genomics and Disease Group, Centre for Genomic Regulation (CRG), Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Bustamante
authors.affiliation: Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.|Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.|Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Peter K
authors.identifier: http://orcid.org/0000-0002-6361-5059
authors.initials: PK
authors.lastname: Joshi
authors.affiliation: Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
authors.forename: James F
authors.initials: JF
authors.lastname: Wilsonx
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Reina-Castillón
authors.affiliation: Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Shin
authors.affiliation: Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Pausova
authors.affiliation: Rotman Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Paus
authors.affiliation: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Sunyer
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pérez-Jurado
authors.affiliation: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Department of Mathematics, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Juan R
authors.initials: JR
authors.lastname: González
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002648:Child; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D015331:Cohort Studies; D005002:Ethiopia; D019143:Evolution, Molecular; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D007360:Intelligence / Q000235:genetics*; D007361:Intelligence Tests; D008253:Macaca mulatta; D008361:Mannosidases / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D057079:Pongo; D051381:Rats; D043323:alpha-Mannosidase
chemical_list: D008361:Mannosidases; C511245:MAN2C1 protein, human; D043323:alpha-Mannosidase