Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence

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

doi:10.1371/journal.pone.0157739

Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence

PLoS One. 2016 Jun 29;11(6):e0157739. doi: 10.1371/journal.pone.0157739. eCollection 2016.

Authors

Alejandro Cáceres^{1

2

3}, Tõnu Esko^{4

5

6

7}, Irene Pappa^{8

9}, Armand Gutiérrez^{10

11

12}, Maria-Jose Lopez-Espinosa^{3

13}, Sabrina Llop^{3

13}, Mariona Bustamante^{1

2

3

14}, Henning Tiemeier^{15

16}, Andres Metspalu^{7

17}, Peter K Joshi¹⁸, James F Wilsonx^{18

19}, Judith Reina-Castillón^{10

11

12}, Jean Shin²⁰, Zdenka Pausova²⁰, Tomáš Paus²¹, Jordi Sunyer^{1

2

3

12}, Luis A Pérez-Jurado^{10

11

12}, Juan R González^{1

2

3

22}

Affiliations

¹ ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
² Universitat Pompeu Fabra, Barcelona, Spain.
³ Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
⁴ Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
⁵ Broad Institute, Cambridge, Massachusetts, United States of America.
⁶ Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, United States of America.
⁷ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁸ School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands.
⁹ Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁰ Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
¹¹ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹² Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
¹³ Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
¹⁴ Genomics and Disease Group, Centre for Genomic Regulation (CRG), Barcelona, Spain.
¹⁵ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
¹⁶ Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁷ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
¹⁸ Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
¹⁹ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
²⁰ Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
²¹ Rotman Research Institute, University of Toronto, Toronto, Ontario, Canada.
²² Department of Mathematics, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.

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.

MeSH terms

Animals
Brain / metabolism*
Child
Chromosome Aberrations*
Chromosome Deletion*
Chromosome Disorders / genetics*
Chromosomes, Human, Pair 15
Cohort Studies
Ethiopia
Evolution, Molecular
Genome, Human
Genotype
Haplotypes*
Homozygote
Humans
In Situ Hybridization, Fluorescence
Intellectual Disability / genetics*
Intelligence / genetics*
Intelligence Tests
Macaca mulatta
Mannosidases / genetics*
Mice
Phenotype
Polymorphism, Single Nucleotide
Pongo
Rats
alpha-Mannosidase

Substances

Mannosidases
MAN2C1 protein, human
alpha-Mannosidase

Grants and funding

This work was supported by the Spanish Ministry of Science and Innovation [MTM2011-26515]; Statistical Genetics Network—GENOMET [MTM2010-09526-E]; Instituto de Salud Carlos III [FIS PI1002512, PI1302481CB06/02/0041, Red INMA G03/176, FIS PI041436, PI081151, PI041705, PS09/00432, FIS-FEDER PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI13/1944, PI14/0891, and Miguel Servet-FEDER CP11/0178 and CP15/0025]; Generalitat de Catalunya [2014SGR1468]; Spanish Ministry of Science and Innovation [SAF2008-00357]; the European Commission [HEALTH-F4-2007-201413, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1]; Fundacio La Marato de TV3, Generalitat de Catalunya [CIRIT 1999SGR 00241]; Conselleria de Sanitat, Generalitat Valenciana to MJLE; Fundacion Roger Torne to MJLE; Canadian Institutes of Health Research to TP and ZP; Heart and Stroke Foundation of Quebec to ZP; The Canadian Foundation for Innovation to ZP; Erasmus Medical Centre, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development [ZonMw]; Netherlands Organization for Health Research and Development [2100.0074]; Estonian Government [SF0180142s08]; Estonian Research Roadmap through Estonian Ministry of Education and Research; Center of Excellence in Genomics [EXCEGEN]; University of Tartu [SP1GVARENG], Estonian Research Council [IUT2-2]; European Regional Development Fund; The Chief Scientist Office of the Scottish Government; The Royal Society; The MRC Human Genetics Unit; Arthritis Research UK and The European Union framework program [LSHG-CT-2006-018947]. LAPJ is funded by the Spanish Ministry of Health (FIS-PI1302481 co-funded by FEDER), the Generalitat de Catalunya (SRG1468-2014), the ICREA-Academia program, and also acknowledges support from the Spanish Ministry of Economy and Competiveness "Programa de Excelencia Maria de Maeztu" (MDM-2014-0370).