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Addiction (Abingdon, England) Mar 2020The use of cannabis has previously been linked to both depression and self-harm; however, the role of genetics in this relationship is unclear. This study aimed to...
BACKGROUND AND AIMS
The use of cannabis has previously been linked to both depression and self-harm; however, the role of genetics in this relationship is unclear. This study aimed to estimate the phenotypic and genetic associations between cannabis use and depression and self-harm.
DESIGN
Cross-sectional data collected through UK Biobank were used to test the phenotypic association between cannabis use, depression and self-harm. UK Biobank genetic data were then combined with consortia genome-wide association study summary statistics to further test the genetic relationships between these traits using LD score regression, polygenic risk scoring and Mendelian randomization methods.
SETTING
United Kingdom, with additional international consortia data.
PARTICIPANTS
A total of 126 291 British adults aged between 40 and 70 years, recruited into UK Biobank.
MEASUREMENTS
Phenotypic outcomes were life-time history of cannabis use (including initial and continued cannabis use), depression (including single-episode and recurrent depression) and self-harm. Genome-wide genetic data were used and assessment centre, batch and the first six principal components were included as key covariates when handling genetic data.
FINDINGS
In UK Biobank, cannabis use is associated with an increased likelihood of depression [odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.59-1.70] and self-harm (OR = 2.85, 95% CI = 2.69-3.01). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Using consortia genome-wide summary statistics, significant genetic correlations are seen between cannabis use and depression [rg = 0.289, standard error (SE) = 0.036]. Polygenic risk scores for cannabis use and depression explain a small but significant proportion of variance in cannabis use, depression and self-harm within a UK Biobank target sample. However, two-sample Mendelian randomization analyses were not significant.
CONCLUSIONS
Cannabis use appeared to be both phenotypically and genetically associated with depression and self-harm. Limitations in statistical power mean that conclusions could not be made on the direction of causality between these traits.
Topics: Adult; Aged; Biological Specimen Banks; Cannabis; Cross-Sectional Studies; Depression; Female; Genome-Wide Association Study; Humans; Lod Score; Male; Marijuana Use; Mendelian Randomization Analysis; Middle Aged; Multifactorial Inheritance; Phenotype; Self-Injurious Behavior; United Kingdom
PubMed: 31833150
DOI: 10.1111/add.14845 -
PloS One 2020The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral genome is an RNA virus consisting of approximately 30,000 bases. As part of testing efforts, whole...
The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral genome is an RNA virus consisting of approximately 30,000 bases. As part of testing efforts, whole genome sequencing of human isolates has resulted in over 1,600 complete genomes publicly available from GenBank. We have performed a comparative analysis of the sequences, in order to detect common mutations within the population. Analysis of variants occurring within the assembled genomes yields 417 variants occurring in at least 1% of the completed genomes, including 229 within the 5' untranslated region (UTR), 152 within the 3'UTR, 2 within intergenic regions and 34 within coding sequences.
Topics: 3' Untranslated Regions; 5' Untranslated Regions; Betacoronavirus; Genetic Linkage; Genome, Viral; Linkage Disequilibrium; Lod Score; Mutation; SARS-CoV-2; Sequence Analysis, RNA; Whole Genome Sequencing
PubMed: 33152019
DOI: 10.1371/journal.pone.0241535 -
The American Journal of Hospice &... Feb 2021Interstitial lung diseases (ILDs) comprise a heterogeneous group of fibrotic, progressive pulmonary diseases characterized by poor end-of-life care and hospital deaths....
BACKGROUND
Interstitial lung diseases (ILDs) comprise a heterogeneous group of fibrotic, progressive pulmonary diseases characterized by poor end-of-life care and hospital deaths. In 2012, we launched our Multidisciplinary Collaborative (MDC) ILD clinic to deliver integrated palliative approach throughout disease trajectory to improve care. We sought to explore the effects of palliative care and other factors on location of death (LOD) of patients with ILD.
METHODS
The MDC-ILD clinic implemented a palliative care bundle including advance care planning (ACP), opiates use, allied health home care engagement, and use of supplemental oxygen and early caregiver engagement in care. Data from patients with ILD who attended the clinic and died between 2012 and 2019 were used to generate scores representing the components and duration of palliative care (palliative care bundle score) and caregiver involvement (caregiver engagement score). We examined the impact of these scores on patients' LOD.
RESULTS
A total of 92 MDC-ILD clinic patients were included, 57 (62%) had home or hospice deaths. Patients who died at home or hospice had higher palliative care bundle scores (10.0 ± 4.0 vs 7.8 ± 3.9, = .01) and caregiver engagement scores (1.7 ± 0.6 vs 1.3 ± 0.7, = .01) compared to those who died in hospital. Patients were 1.13 times more likely to die at home or hospice following a 1-point increase in palliative care bundle score (95% CI: 1.01-1.29, = .04) and 2.38 times more likely following a 1-point increase in caregiver engagement score (95% CI: 1.17-5.15, = .02).
CONCLUSIONS
Home and hospice deaths are feasible in ILD. Early initiation of palliative care bundle components such as ACP discussions, symptom self-management, caregiver engagement, and close collaboration with allied health home care supports can promote adherence to patient preference for home or hospice deaths.
Topics: Advance Care Planning; Humans; Lung Diseases, Interstitial; Palliative Care; Retrospective Studies; Terminal Care
PubMed: 32431183
DOI: 10.1177/1049909120924995 -
PloS One 2022Otosclerosis (OTSC) is the primary form of conductive hearing loss characterized by abnormal bone remodelling within the otic capsule of the human middle ear. A genetic... (Meta-Analysis)
Meta-Analysis
Otosclerosis (OTSC) is the primary form of conductive hearing loss characterized by abnormal bone remodelling within the otic capsule of the human middle ear. A genetic association of the RELN SNP rs3914132 with OTSC has been identified in European population. Previously, we showed a trend towards association of this polymorphism with OTSC and identified a rare variant rs74503667 in a familial case. Here, we genotyped these variants in an Indian cohort composed of 254 OTSC cases and 262 controls. We detected a significant association of rs3914132 with OTSC (OR = 0.569, 95%CI = 0.386-0.838, p = 0.0041). To confirm this finding, we completed a meta-analysis which revealed a significant association of the rs3914132 polymorphism with OTSC (Z = 6.707, p<0.0001) across different ethnic populations. Linkage analysis found the evidence of linkage at RELN locus (LOD score 2.1059) in the OTSC family which has shown the transmission of rare variant rs74503667 in the affected individuals. To understand the role of RELN and its receptors in the development of OTSC, we went further to perform a functional analysis of RELN/reelin. Here we detected a reduced RELN (p = 0.0068) and VLDLR (p = 0.0348) mRNA levels in the otosclerotic stapes tissues. Furthermore, a reduced reelin protein expression by immunohistochemistry was confirmed in the otosclerotic tissues. Electrophoretic mobility shift assays for rs3914132 and rs74503667 variants revealed an altered binding of transcription factors in the mutated sequences which indicates the regulatory role of these variations in the RELN gene regulation. Subsequently, we showed by scanning electron microscopy a change in stapes bone morphology of otosclerotic patients. In conclusion, this study evidenced that the rare variation rs74503667 and the common polymorphism rs3914132 in the RELN gene and its reduced expressions that were associated with OTSC.
Topics: Genetic Predisposition to Disease; Genotype; Humans; Otosclerosis; Polymorphism, Single Nucleotide; Reelin Protein
PubMed: 35658052
DOI: 10.1371/journal.pone.0269558 -
Journal of Animal Science Jan 2023The swine inflammation and necrosis syndrome (SINS) is a syndrome visually characterized by the presence of inflamed and necrotic skin at extreme body parts, such as the...
The swine inflammation and necrosis syndrome (SINS) is a syndrome visually characterized by the presence of inflamed and necrotic skin at extreme body parts, such as the teats, tail, ears, and claw coronary bands. This syndrome is associated with several environmental causes, but knowledge of the role of genetics is still limited. Moreover, piglets affected by SINS are believed to be phenotypically more susceptible to chewing and biting behaviors from pen mates, which could cause a chronic reduction in their welfare throughout the production process. Our objectives were to 1) investigate the genetic basis of SINS expressed on piglets' different body parts and 2) estimate SINS genetic relationship with post-weaning skin damage and pre and post-weaning production traits. A total of 5,960 two to three-day-old piglets were scored for SINS on the teats, claws, tails, and ears as a binary phenotype. Later, those binary records were combined into a trait defined as TOTAL_SINS. For TOTAL_SINS, animals presenting no signs of SINS were scored as 1, whereas animals showing at least one affected part were scored as 2. Apart from SINS traits, piglets had their birth weight (BW) and weaning weight (WW) recorded, and up to 4,132 piglets were later evaluated for combined skin damage (CSD), carcass backfat (BF), and loin depth (LOD). In the first set of analyses, the heritability of SINS on different body parts was estimated with single-trait animal-maternal models, and pairwise genetic correlations between body parts were obtained from two-trait models. Later, we used four three-trait animal models with TOTAL_SINS, CSD, and an alternative production trait (i.e., BW, WW, LOD, BF) to access trait heritabilities and genetic correlations between SINS and production traits. The maternal effect was included in the BW, WW, and TOTAL_SINS models. The direct heritability of SINS on different body parts ranged from 0.08 to 0.34, indicating that reducing SINS incidence through genetic selection is feasible. The direct genetic correlation between TOTAL_SINS and pre-weaning growth traits (BW and WW) was favorable and negative (from -0.40 to -0.30), indicating that selection for animals genetically less prone to present signs of SINS will positively affect the piglet's genetics for heavier weight at birth and weaning. The genetic correlations between TOTAL_SINS and BF and between TOTAL_SINS and LOD were weak or not significant (-0.16 to 0.05). However, the selection against SINS was shown to be genetically correlated with CSD, with estimates ranging from 0.19 to 0.50. That means that piglets genetically less likely to present SINS signs are also more unlikely to suffer CSD after weaning, having a long-term increase in their welfare throughout the production system.
Topics: Pregnancy; Female; Animals; Swine; Weaning; Parturition; Phenotype; Birth Weight; Inflammation; Necrosis; Body Weight; Swine Diseases
PubMed: 36860185
DOI: 10.1093/jas/skad067 -
Archives of Sexual Behavior Nov 2021Male sexual orientation is influenced by environmental and complex genetic factors. Childhood gender nonconformity (CGN) is one of the strongest correlates of...
Male sexual orientation is influenced by environmental and complex genetic factors. Childhood gender nonconformity (CGN) is one of the strongest correlates of homosexuality with substantial familiality. We studied brothers in families with two or more homosexual brothers (409 concordant sibling pairs in 384 families, as well as their heterosexual brothers), who self-recalled their CGN. To map loci for CGN, we conducted a genome-wide linkage scan (GWLS) using SNP genotypes. The strongest linkage peaks, each with significant or suggestive two-point LOD scores and multipoint LOD score support, were on chromosomes 5q31 (maximum two-point LOD = 4.45), 6q12 (maximum two-point LOD = 3.64), 7q33 (maximum two-point LOD = 3.09), and 8q24 (maximum two-point LOD = 3.67), with the latter not overlapping with previously reported strongest linkage region for male sexual orientation on pericentromeric chromosome 8. Family-based association analyses were used to identify associated variants in the linkage regions, with a cluster of SNPs (minimum association p = 1.3 × 10) found at the 5q31 linkage peak. Genome-wide, clusters of multiple SNPs in the 10 to 10 p-value range were found at chromosomes 5p13, 5q31, 7q32, 8p22, and 10q23, highlighting glutamate-related genes. This is the first reported GWLS and genome-wide association study on CGN. Further increasing genetic knowledge about CGN and its relationships to male sexual orientation should help advance our understanding of the biology of these associated traits.
Topics: Gender Identity; Genetic Linkage; Genome-Wide Association Study; Heterosexuality; Homosexuality, Male; Humans; Male; Siblings
PubMed: 34518958
DOI: 10.1007/s10508-021-02146-x -
Frontiers in Aging Neuroscience 2021Modular organization reflects the activity patterns of our brain. Different disease states may lead to different activity patterns and clinical features. Early onset...
Modular organization reflects the activity patterns of our brain. Different disease states may lead to different activity patterns and clinical features. Early onset depression (EOD) and late onset depression (LOD) share the same clinical symptoms, but have different treatment strategies and prognosis. Thus, explored the modular organization of EOD and LOD might help us understand their pathogenesis. The study included 82 patients with late life depression (EOD 40, LOD 42) and 90 healthy controls. We evaluated the memory, executive function and processing speed and performed resting-stage functional MRI for all participants. We constructed a functional network based on Granger causality analysis and carried out modularity, normalized mutual information (NMI), Phi coefficient, within module degree z-score, and participation coefficient analyses for all the participants. The Granger function network analysis suggested that the functional modularity was different among the three groups ( = 0.0300), and NMI analysis confirmed that the partition of EOD was different from that of LOD ( = 0.0190). Rh.10d.ROI (polar frontal cortex) and Rh.IPS1.ROI (dorsal stream visual cortex) were shown to be the potential specific nodes in the modular assignment according to the Phi coefficient ( = 0.0002, = 0.0744 & = 0.0004, = 0.0744). This study reveal that the functional modularity and partition were different between EOD and LOD in Granger function network. These findings support the hypothesis that different pathological changes might exist in EOD and LOD.
PubMed: 33633563
DOI: 10.3389/fnagi.2021.625175 -
Clinical Genetics Jun 2023Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS)....
Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to nonsense mediated decay (NMD). Treating the fibroblasts with an NMD inhibitor, cycloheximide, greatly improved the detection of the pseudoexon-containing transcript. Family members with the FBN1 variant had later onset aortic events and fewer MFS systemic features than typical for individuals with haploinsufficiency of FBN1. Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies.
Topics: Humans; Marfan Syndrome; Fibrillin-1; Mutation; Phenotype; Aortic Diseases
PubMed: 36861389
DOI: 10.1111/cge.14322 -
Archives of Sexual Behavior Nov 2021Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors.... (Meta-Analysis)
Meta-Analysis
Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors. Individual genome-wide linkage studies (GWLS) have been conducted, but not jointly analyzed. Two main datasets account for > 90% of the published GWLS concordant sibling pairs on the trait and are jointly analyzed here: MGSOSO (Molecular Genetic Study of Sexual Orientation; 409 concordant sibling pairs in 384 families, Sanders et al. (2015)) and Hamer (155 concordant sibling pairs in 145 families, Mustanski et al. (2005)). We conducted multipoint linkage analyses with Merlin on the datasets separately since they were genotyped differently, integrated genetic marker positions, and combined the resultant LOD (logarithm of the odds) scores at each 1 cM grid position. We continue to find the strongest linkage support at pericentromeric chromosome 8 and chromosome Xq28. We also incorporated the remaining published GWLS dataset (on 55 families) by using meta-analytic approaches on published summary statistics. The meta-analysis has maximized the positional information from GWLS of currently available family resources and can help prioritize findings from genome-wide association studies (GWAS) and other approaches. Although increasing evidence highlights genetic contributions to male sexual orientation, our current understanding of contributory loci is still limited, consistent with the complexity of the trait. Further increasing genetic knowledge about male sexual orientation, especially via large GWAS, should help advance our understanding of the biology of this important trait.
Topics: Female; Genetic Linkage; Genome, Human; Genome-Wide Association Study; Humans; Lod Score; Male; Sexual Behavior
PubMed: 34080073
DOI: 10.1007/s10508-021-02035-3 -
Genome Medicine Aug 2021Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from...
BACKGROUND
Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood.
METHODS
We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function.
RESULTS
Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network.
CONCLUSIONS
Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.
Topics: Adipocytes; Adipose Tissue; Adiposity; Aged; Algorithms; Biomarkers; Body Mass Index; Cells, Cultured; Computational Biology; Diabetes Mellitus, Type 2; Disease Susceptibility; Gene Expression Profiling; Gene Expression Regulation; Gene Knockdown Techniques; Gene Regulatory Networks; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Lod Score; Male; Middle Aged; Obesity, Abdominal; T-Box Domain Proteins; Trans-Activators; Waist-Hip Ratio
PubMed: 34340684
DOI: 10.1186/s13073-021-00939-2