Paternal age explains a major portion of de novo germline mutation rate variability in healthy individuals

De novo mutations (DNM) are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.

BackgroundCohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits.MethodsClinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations.ResultsWe identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population.ConclusionWe suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n=539) and controls (n=265) from New-York, and PD patients (n=551), rapid eye movement sleep behavior disorder (RBD) patients (n=351) and controls (n=956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency>0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (OR=1.22, 95%CI 1.02-1.47, p=0.03) but with significant heterogeneity (p=0.048). Removing one study that introduced the heterogeneity resulted in nonsignificant association (OR=1.11, 95%CI 0.92-1.35, p=0.27, heterogeneity p=0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p=0.75), and no cumulative effect of carrying more than one MC1R variant was found. The current study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD

Genetic risk factors of childhood onset schizophrenia

Schizophrenia is a severe psychiatric disorder that affects approximately 1% of the general population. Childhood Onset Schizophrenia (COS) is a rare form of schizophrenia diagnosed during childhood (i.e. 6 to 13 years of age). The signs and symptoms of this early form of schizophrenia are continuous with those observed for adult schizophrenia and as such they equally impair the ability of those who are affected. Relatives who are genetically closer to a schizophrenic patient are more likely to develop the disorder themselves, and there is considerable interest in specific genetic mechanisms involved in its transmission. To this day the number of studies that examined the genetic risk associated to COS remains limited and only a few of those studies were focused on the identification of causative genes. With the advent of high-throughput sequencing instruments and whole exome capture arrays, genetic studies of schizophrenia recently tested the implication of de novo variants (variant not inherited from one of the two parents). The first chapter of this thesis describes an investigation of de novo variants across the entire coding regions (whole exome) of individuals diagnosed with COS. Our results showed such COS cases appear to present an increased number of missense variants that are predicted to have deleterious impact suggesting that de novo variants could represent an important aspect of the genetic architecture that underlies the development of COS. The following chapter describes a reexamination of the same whole exome sequencing (WES) data to identify inherited recessive variants. This analysis revealed an enrichment of disease related variants across the X-linked genes of male patients. Interestingly, human brain transcriptome data derived from the general population shows those X-linked genes are highly expressed in the brain. Overall these results represent the first published reports linking COS to single nucleotide variants identified using a tandem high throughput sequencing and genome wide approach (exome). The genes identified in our two studies represent a list of potential genetic risk factors linked to COS, which in turn provide clues about the pathogenicity of this complex disorder.La schizophrénie est un trouble psychiatrique sévère qui touche approximativement 1% de la population générale. La schizophrénie à début précoce est une forme rare de schizophrénie qui se manifeste pendant l'enfance (entre 6 à 13 ans). Des études antérieures ont démontré que les symptômes de cette forme de schizophrénie de l'enfance sont en continuité avec ceux observés chez les adolescents et adultes qui souffrent de la schizophrénie. Peu d'études génétiques ont été réalisées pour la schizophrénie de l'enfance et encore moins ont été axés sur l'identification de gènes causatifs. Avec l'avènement des technologies de séquençage à haut débit et le développement de systèmes permettant de capturer l'ensemble des séquences codantes (exome), les études génétiques portant sur la schizophrénie ont testé la contribution des variations de novo (variations non transmises par l'un des deux parents). Le premier chapitre de la thèse décrit l'identification de variations de novo dans l'ensemble des séquences codantes du génome (exome) de cas ayant reçu un diagnostic de schizophrénie de l'enfance. Nous avons observé une augmentation du nombre de variations faux-sens pour lesquels les outils de prédictions indiquent un impact délétère important. Nos résultats suggèrent que les variations de novo pourraient représenter une part importante de l'architecture génétique de la schizophrénie de l'enfance. La seconde partie de la thèse décrit une étude (faites à partir des mêmes données d'exomes) visant à identifier les variations récessives transmise. Les résultats de cette seconde analyse révèlent un enrichissement des variations au niveau de gènes liés au chromosome X chez les garçons masculins. Fait intéressant, les bases de données transcriptomiques humaine révèlent que ces gènes liés au chromosome X sont fortement exprimés au niveau du cerveau. En résumé, ces résultats sont les premiers à lier la schizophrénie de l'enfance à des variations nucléotidiques simples qui ont été identifiés grâce à une utilisation combinée de séquençage à haut débit au niveau de l'ensemble des séquences codantes du génome (exome). Les gènes identifiés par nos deux études représentent une liste de facteurs de risque génétiques pour la schizophrénie de l'enfance, par la même occasion ceux-ci offrent des indices sur pathogénèse de ce trouble complexe

Increased missense mutation burden of Fatty Acid metabolism related genes in nunavik inuit population.

Nunavik Inuit (northern Quebec, Canada) reside along the arctic coastline where for generations their daily energy intake has mainly been derived from animal fat. Given this particular diet it has been hypothesized that natural selection would lead to population specific allele frequency differences and unique variants in genes related to fatty acid metabolism. A group of genes, namely CPT1A, CPT1B, CPT1C, CPT2, CRAT and CROT, encode for three carnitine acyltransferases that are important for the oxidation of fatty acids, a critical step in their metabolism.Exome sequencing and SNP array genotyping were used to examine the genetic variations in the six genes encoding for the carnitine acyltransferases in 113 Nunavik Inuit individuals.Altogether ten missense variants were found in genes CPT1A, CPT1B, CPT1C, CPT2 and CRAT, including three novel variants and one Inuit specific variant CPT1A p.P479L (rs80356779). The latter has the highest frequency (0.955) compared to other Inuit populations. We found that by comparison to Asians or Europeans, the Nunavik Inuit have an increased mutation burden in CPT1A, CPT2 and CRAT; there is also a high level of population differentiation based on carnitine acyltransferase gene variations between Nunavik Inuit and Asians.The increased number and frequency of deleterious variants in these fatty acid metabolism genes in Nunavik Inuit may be the result of genetic adaptation to their diet and/or the extremely cold climate. In addition, the identification of these variants may help to understand some of the specific health risks of Nunavik Inuit

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n = 539) and controls (n = 265) from New York, and PD patients (n = 551), rapid eye movement sleep behavior disorder (RBD) patients (n = 351), and controls (n = 956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency > 0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (odds ratio = 1.22, 95% confidence interval = 1.02–1.47, p = 0.03) but with significant heterogeneity (p = 0.048). Removing one study that introduced the heterogeneity resulted in nonsignificant association (odds ratio = 1.11, 95% confidence interval, 0.92–1.35, p = 0.27, heterogeneity p = 0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p = 0.75), and no cumulative effect of carrying more than one MC1R variant was found. The present study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n = 539) and controls (n = 265) from New York, and PD patients (n = 551), rapid eye movement sleep behavior disorder (RBD) patients (n = 351), and controls (n = 956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency > 0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (odds ratio = 1.22, 95% confidence interval = 1.02–1.47, p = 0.03) but with significant heterogeneity (p = 0.048). Removing one study that introduced the heterogeneity resulted in nonsignificant association (odds ratio = 1.11, 95% confidence interval, 0.92–1.35, p = 0.27, heterogeneity p = 0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p = 0.75), and no cumulative effect of carrying more than one MC1R variant was found. The present study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD

Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia

International audienceBACKGROUND: Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia. METHODS: A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions. RESULTS: In the exploratory study, ten markers were in significant association with schizophrenia (P\textless0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia. CONCLUSION: This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausibl