Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence.
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 inver...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4927142?pdf=render |
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| author | 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 |
| author_facet | 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 |
| author_sort | Alejandro Cáceres |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T16:08:24Z |
| format | Article |
| id | doaj.art-fa370f2c95534fc8a36addc8ecc74df3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T16:08:24Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-fa370f2c95534fc8a36addc8ecc74df32022-12-22T01:42:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01116e015773910.1371/journal.pone.0157739Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence.Alejandro CáceresTõnu EskoIrene PappaArmand GutiérrezMaria-Jose Lopez-EspinosaSabrina LlopMariona BustamanteHenning TiemeierAndres MetspaluPeter K JoshiJames F WilsonxJudith Reina-CastillónJean ShinZdenka PausovaTomáš PausJordi SunyerLuis A Pérez-JuradoJuan R GonzálezThe 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.http://europepmc.org/articles/PMC4927142?pdf=render |
| spellingShingle | 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 Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence. PLoS ONE |
| title | Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence. |
| title_full | Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence. |
| title_fullStr | Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence. |
| title_full_unstemmed | Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence. |
| title_short | Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence. |
| title_sort | ancient haplotypes at the 15q24 2 microdeletion region are linked to brain expression of man2c1 and children s intelligence |
| url | http://europepmc.org/articles/PMC4927142?pdf=render |
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