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 Perez-Jurado, Juan R. González

Research output: Contribution to journalArticle

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.

LanguageEnglish
Article numbere0157739
JournalPloS one
Volume11
Issue number6
DOIs
Publication statusPublished - 1 Jun 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Cáceres, A., Esko, T., Pappa, I., Gutiérrez, A., Lopez-Espinosa, M. J., Llop, S., ... González, J. R. (2016). Ancient haplotypes at the 15q24.2 microdeletion region are linked to brain expression of MAN2C1 and children's intelligence. PloS one, 11(6), [e0157739]. https://doi.org/10.1371/journal.pone.0157739
Cáceres, Alejandro ; Esko, Tõnu ; Pappa, Irene ; Gutiérrez, Armand ; Lopez-Espinosa, Maria Jose ; Llop, Sabrina ; Bustamante, Mariona ; Tiemeier, Henning ; Metspalu, Andres ; Joshi, Peter K. ; Wilsonx, James F. ; Reina-Castillón, Judith ; Shin, Jean ; Pausova, Zdenka ; Paus, Tomáš ; Sunyer, Jordi ; Perez-Jurado, Luis ; González, Juan R. / Ancient haplotypes at the 15q24.2 microdeletion region are linked to brain expression of MAN2C1 and children's intelligence. In: PloS one. 2016 ; Vol. 11, No. 6.
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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.",
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Cáceres, A, Esko, T, Pappa, I, Gutiérrez, A, Lopez-Espinosa, MJ, Llop, S, Bustamante, M, Tiemeier, H, Metspalu, A, Joshi, PK, Wilsonx, JF, Reina-Castillón, J, Shin, J, Pausova, Z, Paus, T, Sunyer, J, Perez-Jurado, L & González, JR 2016, 'Ancient haplotypes at the 15q24.2 microdeletion region are linked to brain expression of MAN2C1 and children's intelligence', PloS one, vol. 11, no. 6, e0157739. https://doi.org/10.1371/journal.pone.0157739

Ancient haplotypes at the 15q24.2 microdeletion region are linked to brain expression of MAN2C1 and children's intelligence. / Cáceres, Alejandro; Esko, Tõnu; Pappa, Irene; Gutiérrez, Armand; Lopez-Espinosa, Maria Jose; Llop, Sabrina; Bustamante, Mariona; Tiemeier, Henning; Metspalu, Andres; Joshi, Peter K.; Wilsonx, James F.; Reina-Castillón, Judith; Shin, Jean; Pausova, Zdenka; Paus, Tomáš; Sunyer, Jordi; Perez-Jurado, Luis; González, Juan R.

In: PloS one, Vol. 11, No. 6, e0157739, 01.06.2016.

Research output: Contribution to journalArticle

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T1 - Ancient haplotypes at the 15q24.2 microdeletion region are linked to brain expression of MAN2C1 and children's intelligence

AU - Cáceres, Alejandro

AU - Esko, Tõnu

AU - Pappa, Irene

AU - Gutiérrez, Armand

AU - Lopez-Espinosa, Maria Jose

AU - Llop, Sabrina

AU - Bustamante, Mariona

AU - Tiemeier, Henning

AU - Metspalu, Andres

AU - Joshi, Peter K.

AU - Wilsonx, James F.

AU - Reina-Castillón, Judith

AU - Shin, Jean

AU - Pausova, Zdenka

AU - Paus, Tomáš

AU - Sunyer, Jordi

AU - Perez-Jurado, Luis

AU - González, Juan R.

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N2 - 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.

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