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 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

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 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.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/nValenciana 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 cofunded 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

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 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.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/nValenciana 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 cofunded 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

Recombination rate in the region extending the four haplotype blocks M, N, O and P in 15q24.

<p>The figure shows significant reduction of the in the recombination rate of the 3.15Mb segment between 74.71–77.87Mb, as compared with the mean recombination of 10,000 random segments of similar length from chromosome 15.</p

Associations between IQ components and haplotypes M, N, O and P in the 909 Spanish children from the INMA cohort.

<p>Associations between IQ components and haplotypes M, N, O and P in the 909 Spanish children from the INMA cohort.</p

Significant deregulation of <i>MAN2C1</i> expression in the brain for N2, N1a and N1b homozygous.

<p>Numbers in boxplots correspond to the number of haplotypes considered in each group. <i>MAN2C1</i> is ubiquitously over-expressed for N2 homozygous in brain, including pons, cerebellum, frontal cortex, temporal cortex and putamen, but not in occipital cortex, where N1b homozygous are strongly associated with the under-expression of the gene. Significant results in pons, cerebellum, frontal cortex, temporal cortex were obtained from the BRAINeQTL study while those for putamen and occipital cortex where obtained from the BRAINEAC project. Other brain regions in both data-sets showed non-significant associations.</p

Association between N2, N1a and N1b alleles and the gene expressions of <i>MAN2C1</i> and <i>SNUPN</i> in blood and brain.

<p>Logarithm of the expression of <i>MAN2C1</i> and <i>SNUPN</i> in the peripheral blood of 882 Estonians (EGCUT) and 193 deceased un-demented individuals (Myers et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157739#pone.0157739.ref033" target="_blank">33</a>]) as function of the genotype-haplotypes. Numbers in the box-plots correspond to the number of haplotypes. The expression <i>MAN2C1</i> and <i>SNUPN</i> strongly correlated with the three haplotype-genotypes in blood and was validated for N2 (<i>MAN2C1</i>) and N1b (<i>SNUPN</i>) in brain.</p

Haplotype structure of three clades in the N block.

<p><b>A)</b> The MDS analysis in the CD region reveals three clusters that correspond to six different genotypes, with low Mendelian errors of transmission. <b>B)</b> NJ plot showing the phylogenetic relationships between N1a, N1b and N2. The chimp allele is found in the clade N1b.</p

Association between IQ and homozygosity for N2, N1a and N1b.

<p>The figure shows the meta-analysis of three studies (INMA, SYS and GenR) for the association between IQ measures and homozygosity for the N2, N1a and N1b alleles.</p

Long haplotype structures in 15q24.

<p><b>I)</b> Genomic location of the region between 15q24.1-15q24.3 prone to microdeletion and micro duplication syndromes. Segmental duplication blocks A to E are indicated in yellow. Red blocks show the microdeletion cases, adapted from Mefford et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157739#pone.0157739.ref004" target="_blank">4</a>]. The red block marked with MD is a case with the minimum deletion segment (MD in the figure). Also, the green block illustrates the inversion discussed by Antonacci et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157739#pone.0157739.ref002" target="_blank">2</a>] coinciding with the smallest region of overlap (SRO) identified by Magoulas and El-Hattab [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157739#pone.0157739.ref003" target="_blank">3</a>]. <b>II)</b> inveRsion scan over the region. Clear signals of LD differences between SNP blocks are detectable and marked with M, N, O, P. <b>III)</b> Haplotype-genotype clustering of Multidimensional (MDS) Analysis by invClust within segments M, N, O and P. <b>IV)</b> Blocks of LD (r²) between SNPs in the regions M, N, O and P and the haplotype-genotype calls made with invClust.</p