Differences in genomic structure between individuals are ubiquitous features of human genetic variation. Specific copy number variants (CNVs) have been associated with susceptibility to numerous ...complex psychiatric disorders, including attention-deficit-hyperactivity disorder, autism-spectrum disorders and schizophrenia. These disorders often display co-morbidity with low intelligence. Rare chromosomal deletions and duplications are associated with these disorders, so it has been suggested that these deletions or duplications may be associated with differences in intelligence. Here we investigate associations between large (≥500kb), rare (<1% population frequency) CNVs and both fluid and crystallized intelligence in community-dwelling older people. We observe no significant associations between intelligence and total CNV load. Examining individual CNV regions previously implicated in neuropsychological disorders, we find suggestive evidence that CNV regions around SHANK3 are associated with fluid intelligence as derived from a battery of cognitive tests. This is the first study to examine the effects of rare CNVs as called by multiple algorithms on cognition in a large non-clinical sample, and finds no effects of such variants on general cognitive ability.
Narcolepsy is a life‐long neurological disorder with well‐established genetic risk factors. Human leukocyte antigen‐DQB1*06:02 remains the strongest genetic predeterminant; however, polymorphisms in ...genes encoding the T‐cell receptor alpha chain are also strongly linked. This case report shows the inheritance pathway of these genetic markers contributing to narcolepsy onset in a 17‐year‐old female.
Evening-oriented sleep timing preferences have been associated with risk of diabetes, cardiovascular diseases, obesity, psychiatric disorders, and increased mortality. This research aims to explore ...the relationship between diurnal preferences (chronotype), daily habits, metabolic health, and mortality, using longitudinal data from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (6375 participants at inception, recruited in the North of England) with a long follow-up period (up to 35.5 years). Mixed models were used to investigate the influence of aging, socio-demographic, and seasonal factors on sleep timing. Results show that sleep timing shifted towards earlier time with aging. Test seasons influence chronotype of older adults but working schedules challenge seasonality of sleep timing. Moreover, the season of birth may set chronotype in adulthood. Individual chronotype trajectories were clustered using latent class analysis and analyzed against metabolic health and mortality. We observed a higher risk of hypertension in the evening-type cluster compared to morning-type individuals (Odds ratio = 1.88, 95%CI = 1.02/3.47,
= .04). Evening-type cluster was also associated with traits related to lower health such as reduced sport participation, increased risk of depression and psychoticism personality, late eating, and increased smoking and alcohol usage. Finally, Cox regression of proportional hazards was used to study the effects of chronotype on longevity after adjusting for sleep duration, age, gender, smoking, alcohol usage, general health, and social class. The survival analysis (82.6% censored by death) revealed that evening-type chronotype increased the likelihood of mortality (Hazard ratio = 1.15, 95%CI = 1.04/1.26,
= .005). Taken together, chronotype is influenced by aging and seasonal effects. Evening-type preference may have detrimental outcomes for human well-being and longevity.
Background:
Mutations in SCN9A, encoding the alpha subunit of the voltage-gated sodium channel (Nav1.7), have caused severe pain disorders and congenital insensitivity to pain. The aim of this study ...was to validate the previously reported association between a common non-synonymous polymorphism (R1150W, rs6746030) in SCN9A and chronic widespread pain (CWP), in independent population-based cohorts.
Findings:
Genotype data for rs6746030 was available in four population-based cohorts (EPIFUND, the European Male Ageing Study (EMAS), the Framingham study and the Dyne Steel DNA Bank of Ageing and Cognition). Pain was assessed using body manikins and CWP was scored using American College of Rheumatology (ACR) criteria in all cohorts, except the Framingham study which assessed widespread pain (WP) using ACR criteria on a joint pain homunculus. Controls were subjects who reported no pain. Logistic regression (additive genetic model) was used to test for association between rs6746030 and CWP compared to controls, adjusting for study centre in EMAS. Generalised estimating equation regression was used to test for association between rs6746030 and WP, whilst accounting for relatedness between subjects in the Framingham study. Genotype data for rs6746030 was available for 1071 CWP cases and 3212 controls. There was no significant association between CWP and rs6476030 in individual cohorts or when combined in a fixed-effects meta-analysis (Odds Ratio = 0.96 (95% confidence interval 0.82, 1.11) p = 0.567).
Conclusions:
In contrast to a previous study, no association between a non-synonymous polymorphism in SCN9A and CWP was observed in multiple population-based cohorts.
The relationships between older age and sleep efficiency have traditionally been assessed using cross‐sectional studies that ignore changes within individuals as they age. This research examines the ...determinants of sleep efficiency, the heterogeneity in an individual's sleep efficiency trajectory across a period of up to 27 years in later life and its associations with health. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort (n = 6,375; age 42–94 years) was used in this study. Depression and health data were collected using self‐report validated instruments (Cornell Medical Index, Beck Depression Inventory and Geriatric Depression Scale). Longitudinal sleep and sociodemographic data were collected using a study‐specific self‐report questionnaire. A mixed‐effect model was performed for sleep efficiency with adjustments for time‐invariant and time‐variant predictors. Latent class analysis was used to demonstrate subgroups of sleep efficiency trajectories and associations between sleep efficiency clusters and health history of the participants were investigated. Older adults have decreased sleep efficiency over time, with 18.6% decline between 40 and 100 years of age. Three sleep efficiency trajectory clusters were identified: high (32%), medium (50%) and low sleep efficiency (18%). Belonging to the high sleep efficiency cluster was associated with having lower prevalence of hypertension, circulatory problems, general arthritis, breathing problems and recurrent episodes of depression compared to the low efficiency cluster. Overall, ageing decreases sleep efficiency. However, there are detectable subgroups of sleep efficiency that are related to prevalence of different diseases.
This study aims to examine whether maternal smoking, birth weight, birth month and breastfeeding are associated with COVID-19 infection and hospitalisation. Maternal smoking was positively associated ...with COVID-19 infection. Breastfeeding was negatively associated with COVID-19 infection. The odds of being hospitalised due to COVID-19 were higher among those who had lower birthweight and mothers who were smoking during pregnancy.
•Low birth weight was associated with hospitalisation due to COVID-19.•The odds of contracting COVID-19 were 12% lower among respondents who were breastfed when they were babies.•People who reported that their mother smoked when they were born had 20% higher odds of COVID-19 infection and 24% higher odds of hospitalisation.
The cytokine interleukin 6 (IL-6) has been linked to the pathogenesis of Alzheimer’s disease (AD). This is the first study to investigate the genetic and epigenetic interactions in the control of ...IL-6 in human brain and its relation to AD neuropathology in prefrontal cortex tissues from AD and controls genotyped for the SNP −174 C/G rs1800795, a polymorphic CpG in which the G allele creates a CpG site. Within CC homozygotes there were significantly higher brain levels of IL-6 protein compared to G allele carriers. The C allele that resulted in an absence of methylation at a CpG was also associated with significant changes in methylation at neighboring CpGs. Furthermore, there were significant differences in methylation between CC and CG/GG at CpG sites in the AD and control groups. That DNA methylation was altered in the brains by the presence of rs1800795, which further correlated with protein levels suggests the presence of a polymorphic CpG and genetic-epigenetic interactions in the regulation of IL-6 in the prefrontal cortex within AD brains.
•The IL-6 polymorphism rs1800795 linked to Alzheimer'’s disease changes a CpG site.•CC homozygotes show higher brain levels of IL-6 protein compared to G carriers.•C allele altered methylation at a polymorphic CpG and neighbouring CpGs.•Methylation differed in the brains by the presence of CC and CG/GG genotypes.•Results imply genetic-epigenetic interactions in regulation of IL-6 in AD brains.
Attention-deficit hyperactivity disorder (ADHD) is a highly heritable childhood-onset psychiatric condition characterized by developmentally inappropriate inattention, hyperactivity, and ...impulsiveness. The pathophysiology of ADHD is currently unknown. However, the therapeutic effects of stimulant medication together with findings from animal and neuroimaging studies as well as from several molecular genetic studies of the dopamine receptor D4 gene and dopamine transporter gene have implicated involvement of the dopaminergic system. To test the dopaminergic hypothesis further, we have looked for association between ADHD and alleles of seven dopamine-related candidate genes using a family-based association approach in a sample of 150 children diagnosed with ADHD. We tested polymorphisms in genes encoding three dopamine receptors (DRD3, DRD4, and DRD5) and four dopamine-relevant enzymes: tyrosine hydroxylase tyrosine hydroxylase (TH), dopamine beta hydroxylase (DbetaH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). We were unable to detect a significant association with any of the polymorphisms genotyped, although there was a trend for preferential transmission of the DRD5 148 bp marker allele and the MAOA 122 bp marker allele. We conclude that none of the alleles we have tested makes a major contribution to ADHD, although much larger samples are required to exclude small effects.
Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social ...isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E−08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.
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