Polygenic score for sleep duration. Association with cognition.

STUDY OBJECTIVES: Age-related changes in sleep include a reduction in total sleep time and a greater incidence of sleep disorders, and are also an integral part of neurodegenerations. In the present study, we aimed to: a) identify common genetic variants that may influence self-reported sleep duration, and b) examine the association between the identified genetic variants and performance in different cognitive domains. METHODS: A sample of 197 cognitively healthy participants, aged 20-80 years, mostly non-Hispanic Whites (69%), were selected from the Reference Abilities Neural Network and the Cognitive Reserve study. Each participant underwent an evaluation of sleep function and assessment of neuropsychological performance on global cognition and four different domains (memory, speed of processing, fluid reasoning, language). Published GWAS summary statistics from a Polygenic Score (PS) for sleep duration in a large European ancestry cohort (N = 30,251) were used to derive a PS in our study sample. Multivariate linear models were used to test the associations between the PS and sleep duration and cognitive performance. Age, sex, and education were used as covariates. Secondary analyses were conducted in three age-groups (young, middle, old). RESULTS: Higher PS was linked to longer sleep duration and was also associated with better performance in global cognition, fluid reasoning, speed of processing, and language, but not memory. Results especially for fluid reasoning, language, and global cognition were driven mostly by the young group. CONCLUSIONS: Our study replicated the previously reported association between sleep-PS and longer sleep duration. We additionally found a significant association between the sleep-PS and cognitive function. Our results suggest that common genetic variants may influence the link between sleep duration and cognitive health.

[Domestic exposure to moulds and mite allergens in Parisian patients]. / Exposition domestique aux moisissures et aux allergènes d'acariens de patients parisiens.

INTRODUCTION: Moulds and mite allergens present in indoor environments are well known for their effects on respiratory health. METHODS: From 2011 to 2015, the Paris Service for Environmental Health (SPSE) conducted investigations in 293 dwellings following medical referral. These audits included fungal analysis of air (in 12% of dwellings), in mattress surface and floor dust (24%), and mite allergen quantifications in mattresses and carpets (18%). RESULTS: Indoor air fungal concentrations are not significantly different from those in outdoor air. When there is no ventilation or when the system is malfunctioning, an increase in indoor/outdoor air ratios is observed, indicating mould enrichment in the dwelling's indoor air. With regard to house dust samples, fungal spore concentrations vary according to the media from which samples were collected. Mattress fungal contamination is higher in dwellings where observed surface moulds exceed 1 per square meter. In the same way Der p1 mite allergens levels are greater in mattress dust in dwellings where mould contamination is visible. CONCLUSIONS: This study describes the levels of contamination in the dwellings of Parisian patients.

A Dopamine Receptor genetic variant enhances perceptual speed in cognitive healthy subjects.

Cognition is under strong genetic control, yet the specific genes are unknown. To investigate genetic influences on specific cognitive domains, 153 cognitive healthy subjects of European ancestry from the Reference Abilities Study (RANN) were genotyped for 1,160 variants within 446 neuropsychiatric genes. Adjusted linear regression models evaluated the association between the genetic variants and four reference abilities, which capture variance in age-related cognitive function (Vocabulary, Episodic Memory, Perceptual Speed, and Reasoning). 159 variants nominally significant in the RANN cohort were then re-evaluated in an independent cohort of 868 cognitive healthy subjects from the Religious Orders Study and Rush Memory Aging Project. Meta-analysis yielded a Bonferroni adjusted statistically significant association between perceptual speed and a variant located in the promoter of the dopamine receptor D4 gene, rs3756450 (ß=0.23, SE=0.05, P meta =2.3 × 10-5). Our data suggest that genetic variation in a dopamine pathway gene influences perceptual speed performance in cognitively healthy individuals.

Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis.

OBJECTIVE: The aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families. METHODS: Genome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family. RESULTS: Genome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele. CONCLUSION: A potentially novel functional OA susceptibility variant was identified by targeted re-sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis.

A specific CBP/p300-dependent gene expression programme drives the metabolic remodelling in late stages of spermatogenesis.

Histone hyperacetylation is thought to drive the replacement of histones by transition proteins that occur in elongating spermatids (ElS) after a general shut down of transcription. The molecular machineries underlying this histone hyperacetylation remain still undefined. Here, we focused our attention on the role of Cbp and p300 in histone hyperacetylation and in the preceding late-gene transcriptional activity in ElS. A strategy was designed to partially deplete Cbp and p300 in ElS. These cells progressed normally through spermiogenesis and showed normal histone hyperacetylation and removal. However, a genome-wide transcriptomic analysis, performed in the round spermatids (RS) and ElS, revealed the existence of a gene regulatory circuit encompassing genes presenting high expression levels in pre-meiotic cells, undergoing a repressed state in spermatocytes and early post-meiotic cells, but becoming reactivated in ElS, just prior to the global shutdown of transcription. Interestingly, this group of genes was over-represented within the genes affected by Cbp/p300 knock down and were all involved in metabolic remodelling. This study revealed the occurrence of a tightly regulated Cbp/p300-dependent gene expression programme that drives a specific metabolic state both in progenitor spermatogenic cells and in late transcriptionally active spermatids and confirmed a special link between Cpb/p300 and cell metabolism programming previously shown in somatic cells.

Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory.

OBJECTIVE: Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes. METHODS: Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education. RESULTS: Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (ß = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (ß = -0.44, SE = 0.09, p = 0.009 and ß = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (ß = 0.26, SE = 0.10, p = 0.010). CONCLUSIONS: MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease.

Biomechanical analysis of postural strategies over the first two months following anterior cruciate ligament reconstruction.

To assess the postural strategies developed over the first 2 months following surgery by ACL patients during rehabilitation and highlight the sensory-motor impairment recovery, 21 patients were measured at three timeframes. Three two-legged standing conditions were assessed: with the eyes open, with the eyes closed either wearing or not wearing a knee orthosis. The results indicate that the weight-bearing asymmetry, initially observed (i.e., 56-44% of body-weight), disappeared progressively during rehabilitation (51-49%). The comparison of the plantar center-of-pressure displacements under both sound and operated legs demonstrated noticeable differences that also tended to decrease but without reaching a matched behavior during the last measures. These effects were seen in both eyes open and eyes closed conditions with the greatest effects in the latter condition. Wearing a knee orthosis inferred no particular changes in the postural control behaviors. These data could be used as benchmarks for highlighting the effects on undisturbed postural control of various surgery techniques and/or rehabilitation protocols.

Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach.

AIMS/HYPOTHESIS: In the present study we investigated potential associations of a set of 45 single nucleotide polymorphisms (SNP) in 20 candidate genes on eight chromosomes with diabetic nephropathy (DN) in type 2 diabetes mellitus. We aimed to compare two methodological approaches suitable for analysing susceptibility to complex traits: single- and multi-locus analyses. MATERIALS AND METHODS: The study comprised a total of 647 subjects in one of three groups: diabetes with or without DN, or no diabetes. Genotypes were detected by PCR-based methodology (PCR only, PCR plus RFLP, or allele-specific PCR). Haplotypes were inferred in silico. Set association (tested using SUMSTAT software) was used for multilocus analysis. RESULTS: After correction for multiple comparisons, only one SNP, in the gene encoding the receptor of advanced glycation end products, AGER 2184A/G (gene symbol formerly known as RAGE) showed a significant association with DN (p = 0.0006) in single-locus analysis. In multi-locus analysis, six SNPs exhibited a significant association with DN: four SNPs on chromosome 6p (AGER 2184A/G, LTA 252A/G, EDN1 8002G/A and AGER -429T/C) and two SNPs on chromosome 7q (NOS3 774C/T and NOS3 E298D), omnibus p = 0.033. Haplotype analysis revealed significant differences between DN and control groups in haplotype frequencies on chromosome 6 (p = 0.0002); however, there were no significant difference in the frequencies of the NOS3 haplotypes on chromosome 7. Logistic regression analysis identified SNPs AGER 2184A/G and NOS3 774C/T, together with diabetes duration and HbA1c, as significant predictors of DN. Testing for interactions between SNPs on chromosomes 6 and 7 did not provide significant evidence for epistatic interaction. CONCLUSIONS/INTERPRETATION: Using the set-association approach we identified significant associations of several SNPs on chromosomes 6 and 7 with DN. The single- and multi-locus analyses represent complementary methods.

Detection of HCV RNA in saliva of patients with hepatitis C virus infection by using a highly sensitive test.

Hepatitis C virus (HCV) is transmitted primarily by direct percutaneous exposures to blood. Since HCV RNA has been found in saliva, it has been suggested that saliva might also be a source of infection. HCV RNA in saliva from plasma HCV RNA positive patients was tested by a highly sensitive PCR method. HCV RNA was detected in 32 out of 61 saliva specimens (52.4%). No correlation was found between the presence of HCV in saliva and age, sex, identified risk factors for HCV infection, time lapsed since the diagnosis, transaminases and alkaline phosphatase values and stimulated salivary flow. A statistically significant relation between plasma HCV RNA viral load and saliva HCV RNA detection was observed (P<0.001). In conclusion, HCV RNA is often present in saliva of HCV infected patients, with plasma viral load being the only known predictable factor. Further studies on salivary HCV RNA are needed.

Sequence variation of two hypervariable short tandem repeats at the D22S683 and D6S477 loci.

For two short tandem repeats at the D22S683 and D6S477 loci, 30 and 22 selected alleles, respectively were sequenced. A total of 20 different alleles were found for the D22S683 locus and 12 alleles for the D6S477 locus. In both systems the alleles were designated according to the total number of repeats. D22S683 is a hypervariable STR consisting of blocks of (TATC) repeats with a basic sequence structure (TATATC)n (TATC)n (ATC)0-1 (TATC)n. The D6S477 locus consists of blocks of (TCTA) repeats with a basic sequence structure (TCTA)n (TA)1 (TCTA)0-2 (TA)0-1 (TCTA)n. Population data showed a heterozygosity of 0.89 for D22S683 and 0.75 for D6S477. These STRs are promising markers for forensic genetics as they are robust and can be easily included in multiplexes.

Sequence variation of a variable short tandem repeat at the D18S535 locus.

A short tandem repeat in the D18S535 locus was sequenced in 25 selected alleles. A total of 8 different alleles were found which can be designated according to the total number of repeats. This STR is a simple hypervariable STR consisting of blocks of (GATA) repeats with a basic sequence structure (GATA)1(GACA)1(GATA)1 (GAT)1(GATA)9-16. Population data showed that this is a highly polymorphic STR with a heterozygosity of more than 0.80, a simple structure and small size (130-158 bp) which makes this an interesting DNA polymorphism for forensic and genetic purposes.

Sequence variation of a hypervariable short tandem repeat at the D1S1656 locus.

A short tandem repeat at the D1S1656 locus was sequenced in 45 selected alleles and 13 different alleles were found which were designated according to the total number of repeats. This STR is a compound hypervariable STR consisting of blocks of (TAGR) repeats with a basic sequence structure (TAGA)4(TGA)0-1(TAGA)6-16(TAGG)0-1(TG)5. The presence of a TGA, probably due to an A deletion in the fifth TAGA repeat leads to intermediate a.3 alleles. Population data showed that this is a highly polymorphic STR with a heterozygosity of more than 0.89. This fact together with its simple structure and small size (129-168 bp) makes this STR one of the most interesting DNA polymorphisms for forensic and genetic purposes.