Associations of polysocial risk score, lifestyle and genetic factors with incident psoriasis: a larger-scale prospective cohort study.

OBJECTIVES: The impact of polysocial risk score (PsRS), a composite measure of multiple social risk factors, on the development of psoriasis remains unclear. Moreover, the potential modifying effects of lifestyle and genetic susceptibility on the relationship between PsRS and psoriasis risk require further exploration. STUDY DESIGN: This was a prospective cohort study conducted among UK Biobank. METHODS: In this study, we analyzed 331,631 participants enrolled in the UK Biobank cohort. To derive the PsRS, we utilized a summative strategy, amalgamating six social determinants of health derived from three domains: socio-economic status, psychosocial factors, and neighborhood and living environment consistently linked to incident psoriasis. Cox proportional hazard models were used to assess the associations between PsRS and psoriasis incidence. Furthermore, we constructed a lifestyle score and a genetic risk score to explore the potential modifying effects of these factors on the relationship between PsRS and psoriasis risk. RESULTS: Compared with individuals with a low PsRS (≤1), those with intermediate PsRS (2-4) and high PsRS (≥5) had 1.20 (95% confidence interval [CI], 1.06-1.36) and 1.53 (95% CI, 1.31-1.78) times higher risks of developing psoriasis, respectively. Our findings revealed an additive interaction between PsRS and genetic susceptibility. Moreover, it was found that individuals with high PsRS and unhealthier lifestyles had a 2.60 times higher risk of developing psoriasis than those with lower PsRS and healthier ones. CONCLUSIONS: Our study results imply that an elevated PsRS is linked to a heightened risk of psoriasis, which is further influenced by genetic factors. Our results also indicate that greater social vulnerability and unhealthier lifestyle may synergistically contribute to the additional risk of psoriasis.

Hypermethylation at CREBBP Is Associated with Cognitive Impairment in a Mexican American Cohort.

BACKGROUND: The aging Mexican American (MA) population is the fastest growing ethnic minority group in the US. MAs have a unique metabolic-related risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI), compared to non-Hispanic whites (NHW). This risk for cognitive impairment (CI) is multifactorial involving genetics, environmental, and lifestyle factors. Changes in environment and lifestyle can alter patterns and even possibly reverse derangement of DNA methylation (a form of epigenetic regulation). OBJECTIVE: We sought to identify ethnicity-specific DNA methylation profiles that may be associated with CI in MAs and NHWs. METHODS: DNA obtained from peripheral blood of 551 participants from the Texas Alzheimer's Research and Care Consortium was typed on the Illumina Infinium® MethylationEPIC chip array, which assesses over 850K CpG genomic sites. Within each ethnic group (N = 299 MAs, N = 252 NHWs), participants were stratified by cognitive status (control versus CI). Beta values, representing relative degree of methylation, were normalized using the Beta MIxture Quantile dilation method and assessed for differential methylation using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. RESULTS: Two differentially methylated sites were significant: cg13135255 (MAs) and cg27002303 (NHWs) based on an FDR p < 0.05. Three suggestive sites obtained were cg01887506 (MAs) and cg10607142 and cg13529380 (NHWs). Most methylation sites were hypermethylated in CI compared to controls, except cg13529380 which was hypomethylated. CONCLUSION: The strongest association with CI was at cg13135255 (FDR-adjusted p = 0.029 in MAs), within the CREBBP gene. Moving forward, identifying additional ethnicity-specific methylation sites may be useful to discern CI risk in MAs.

African ancestry GWAS of dementia in a large military cohort identifies significant risk loci.

While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

Polygenic risk scores for schizophrenia and major depression are associated with socio-economic indicators of adversity in two British community samples.

Schizophrenia (SCZ) and major depressive disorder (MDD) are complex psychiatric disorders which contribute substantially to the global burden of disease. Both psychopathologies are heritable with some genetic overlap between them. Importantly, SCZ and MDD have also been found to be associated with environmental risk factors. However, rather than being independent of genetic influences, exposure to environmental risk factors may be under genetic control, known as gene-environment correlation (rGE). In this study we investigated rGE in relation to polygenic risk scores for SCZ and MDD in adults, derived from large genome-wide association studies, across two different British community samples: Understanding Society (USoc) and the National Child Development Study (NCDS). We tested whether established environmental risk factors for SCZ and/or MDD are correlated with polygenic scores in adults and whether these associations differ between the two disorders and cohorts. Findings partially overlapped between disorders and cohorts. In NCDS, we identified a significant correlation between the genetic risk for MDD and an indicator of low socio-economic status, but no significant findings emerged for SCZ. In USoc, we replicated associations between indicators of low socio-economic status and the genetic propensity for MDD. In addition, we identified associations between the genetic susceptibility for SCZ and being single or divorced. Results across both studies provide further evidence that the genetic risk for SCZ and MDD were associated with common environmental risk factors, specifically MDD's association with lower socio-economic status.

Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa.

BACKGROUND: Elucidation of specific and recurrent/founder pathogenic variants (PVs) in BRCA (BRCA1 and BRCA2) genes can make the genetic testing, for breast cancer (BC) and/or ovarian cancer (OC), affordable for developing nations. METHODS: To establish the knowledge about BRCA PVs and to determine the prevalence of the specific and recurrent/founder variants in BRCA genes in BC and/or OC women in North Africa, a systematic review was conducted in Morocco, Algeria, and Tunisia. RESULTS: Search of the databases yielded 25 relevant references, including eleven studies in Morocco, five in Algeria, and nine in Tunisia. Overall, 15 studies investigated both BRCA1 and BRCA2 genes, four studies examined the entire coding region of the BRCA1 gene, and six studies in which the analysis was limited to a few BRCA1 and/or BRCA2 exons. Overall, 76 PVs (44 in BRCA1 and32 in BRCA2) were identified in 196 BC and/or OC patients (129 BRCA1 and 67 BRCA2 carriers). Eighteen of the 76 (23.7%) PVs [10/44 (22.7%) in BRCA1 and 8/32 (25%) in BRCA2] were reported for the first time and considered to be novel PVs. Among those identified as unlikely to be of North African origin, the BRCA1 c.68_69del and BRCA1 c.5266dupC Jewish founder alleles and PVs that have been reported as recurrent/founder variants in European populations (ex: BRCA1 c.181T>G, BRCA1 c1016dupA). The most well characterized PVs are four in BRCA1 gene [c.211dupA (14.7%), c.798_799detTT (14%), c.5266dup (8.5%), c.5309G>T (7.8%), c.3279delC (4.7%)] and one in BRCA2 [c.1310_1313detAAGA (38.9%)]. The c.211dupA and c.5309G>T PVs were identified as specific founder variants in Tunisia and Morocco, accounting for 35.2% (19/54) and 20.4% (10/49) of total established BRCA1 PVs, respectively. c.798_799delTT variant was identified in 14% (18/129) of all BRCA1 North African carriers, suggesting a founder allele. A broad spectrum of recurrent variants including BRCA1 3279delC, BRCA1 c.5266dup and BRCA2 c.1310_1313detAAGA was detected in 42 patients. BRCA1 founder variants explain around 36.4% (47/129) of BC and outnumber BRCA2 founder variants by a ratio of ≈3:1. CONCLUSIONS: Testing BC and/or OC patients for the panel of specific and recurrent/founder PVs might be the most cost-effective molecular diagnosis strategy.

Association of Genome-Wide Polygenic Scores for Multiple Psychiatric and Common Traits in Preadolescent Youths at Risk of Suicide.

Importance: Suicide is the second leading cause of death among youths worldwide, but no available means exist to identify the risk of suicide in this population. Objective: To assess whether genome-wide polygenic scores for psychiatric and common traits are associated with the risk of suicide among preadolescent children and to investigate whether and to what extent the interaction between early life stress (a major environmental risk factor) and polygenic factors is associated with suicidal thoughts and behaviors among youths. Design, Setting, and Participants: This cohort study analyzed the genotype-phenotype data of 11 869 preadolescent children aged 9 to 10 years from the Adolescent Brain and Cognitive Development study. Data were collected from September 1, 2016, to October 21, 2018, and analyzed from August 1, 2020, to January 3, 2021. Using machine learning approaches, genome-wide polygenic scores of 24 complex traits were estimated to investigate their phenome-wide associations and utility for assessing risk of suicidal thoughts and behaviors (suicidal ideation [active, passive, and overall] and suicide attempt). Main Outcomes and Measures: Genome-wide polygenic scores were used to measure 24 traits, including psychiatric disorders, cognitive capacity, and personality and psychological characteristics. The Child Behavior Checklist was used to measure early life stress, and the Family Environment Scale was used to assess family environment. Suicidal ideation and suicide attempts were derived from the computerized version of the Kiddie Schedule for Affective Disorders and Schizophrenia. Results: Among 11 869 preadolescent children in the US, complete data for phenotypic outcomes, genotypes, and covariates were available for 7140 participants in the multiethnic cohort (mean [SD] age, 9.9 [0.6] years; 3588 girls [50.3%]), including 925 participants with suicidal ideation and 63 participants with suicide attempts. Among those 7140 participants, 729 had African ancestry (self-reported race or ethnicity: 569 Black, 71 Hispanic, and 89 other), 276 had admixed American ancestry (self-reported race or ethnicity: 265 Hispanic, 3 White, and 8 other), 150 had East Asian ancestry (self-reported race or ethnicity: 67 Asian, 18 Hispanic, and 65 other), 5718 had European ancestry (self-reported race or ethnicity: 7 Asian, 39 Black, 1142 Hispanic, 3934 White, and 596 other), and 267 had other ancestries (self-reported race or ethnicity: 70 Asian, 13 Black, 126 Hispanic, 48 White, and 10 other). Three genome-wide polygenic scores were significantly associated (false discovery rate P < .05) with suicidal thoughts and behaviors among all participants: attention-deficit/hyperactivity disorder (odds ratio [OR], 1.12; 95% CI, 1.05-1.21; P = .001), schizophrenia (OR, 1.50; 95% CI, 1.17-1.93; P = .002), and general happiness (OR, 0.89; 95% CI, 0.83-0.96; P = .002). In the analysis including only children with European ancestry, 3 additional genome-wide polygenic scores with false discovery rate significance were associated with suicidal thoughts and behaviors: autism spectrum disorder (OR, 1.18; 95% CI, 1.06-1.31; P = .002), major depressive disorder (OR, 1.12; 95% CI, 1.04-1.21; P = .003), and posttraumatic stress disorder (OR, 1.12; 95% CI, 1.04-1.21; P = .004). A significant interaction between genome-wide polygenic scores and environment was found, with genetic risk factors for autism spectrum disorder and the level of early life stress associated with increases in the risk of overall suicidal ideation and overall suicidal thoughts and behaviors (OR, 1.20; 95% CI, 1.07-1.35; P = .002). A machine learning model using multitrait genome-wide polygenic scores and additional self-reported questionnaire data (Child Behavior Checklist and Family Environment Scale) produced a moderately accurate estimate of overall suicidal thoughts and behaviors (area under the receiver operating characteristic curve [AUROC], 0.77; 95% CI, 0.73-0.81; accuracy, 0.67) and suicidal ideation (AUROC, 0.76; 95% CI, 0.72-0.80; accuracy, 0.66) among children with European ancestry only. Among all children in the multiethnic cohort, the integrated model also outperformed the baseline model in estimating the risk of overall suicidal thoughts and behaviors (AUROC, 0.71; 95% CI, 0.67-0.75; accuracy, 0.68) and suicidal ideation (AUROC, 0.75; 95% CI, 0.71-0.78; accuracy, 0.67). Conclusions and Relevance: In this cohort study of preadolescent youths in the US, higher genome-wide polygenic scores for psychiatric disorders, such as attention-deficit/hyperactivity disorder, autism spectrum disorder, posttraumatic stress disorder, and schizophrenia, were significantly associated with a greater risk of suicidal ideation and suicide attempt. The findings and quantitative models from this study may help to identify children with a high risk of suicide, potentially assisting with early screening, intervention, and prevention.

Alpha-1 antitrypsin deficiency and risk of lung cancer in never-smokers: a multicentre case-control study.

BACKGROUND: Lung cancer (LC) is the most commonly diagnosed cancer and the leading cause of cancer-related death in both sexes worldwide. Although the principal risk factor in the western world is tobacco smoking, genetic factors, including alpha-1 antitrypsin deficiency (AATD), have been associated with increased risk. This study is the continuation of an earlier one published by the same group in 2015, aimed at analysing risk of LC in never-smokers, associated with carriers of the AATD genotype. METHODS: A multicentre case-control study was conducted in Spain across the period January 2011 to August 2019. Cases were non-smokers diagnosed with LC, and controls were composed of never-smoking individuals undergoing major non-cancer-related surgery. Data were collected on epidemiological characteristics, exposure to environmental tobacco smoke (ETS), residential radon levels, and alpha-1 antitrypsin (AAT) genotype. RESULTS: The study included 457 cases (42%) and 631 controls (58%), with a predominance of women (72,8%). The most frequent histological type was adenocarcinoma (77.5%), followed by squamous cell carcinoma (7.7%). No association of risk of LC was found with the status of AATD genotype carrier, both overall and broken down by age, sex, or exposure to ETS. CONCLUSIONS: No risk association was found between being a carrier of an AAT deficiency genotype and LC among never-smokers. In order to establish the existence of an association, we consider it important to expand the studies in never smokers in different geographical areas as well as to include patients with previous chronic lung diseases to assess if it influences the risk.

Association between MTHFR C677T polymorphism and risk of coronary artery disease in the Chinese population: meta-analysis.

BACKGROUND: Previous studies have investigated the close association between the MTHFR C677T polymorphism and the risk of coronary heart disease (CAD) in the Chinese population. However, the results remain inconclusive. Therefore, this meta-analysis was performed to derive a more precise estimate of these associations. METHODS: Odds ratios (OR) with 95% confidence intervals (CI) were used to assess the relationship between the MTHFR C677T polymorphism and the risk of CAD. Studies were identified by searching the literature for articles published before 2017. RESULTS: A total of 39 studies comprising 12,101 individuals (6117 cases and 5984 controls) were included. For the allelic model T vs. C, the pooled OR was 1.43 (95% CI: 1.30-1.57, p < 0.0001); for the recessive model TT vs. CC + TC, the pooled OR was 1.48 (95% CI: 1.29-1.70, p < 0.0001); for the dominant model TT + TC vs. CC, the pooled OR was 1.65 (95% CI: 1.43-1.89, p < 0.0001). CONCLUSION: In the subgroup analysis of high-quality studies, an obvious association was observed between the MTHFR C677T polymorphism and CAD risk in the Chinese population.

Identification of the interactions between specific genetic polymorphisms and nutrient intake associated with general and abdominal obesity in middle-aged adults.

BACKGROUND & AIMS: Comprehensive understanding of gene-diet interactions is necessary to establish proper dietary guidelines to prevent and manage general and abdominal obesity. We investigated the role of genetic variants and their interactions with general and abdominal obesity-associated nutrients using a largescale genome-wide association study of Korean adults. METHODS: A total of 50,808 participants from a Korean genome and epidemiology study were included. Dietary intake was assessed using a food frequency questionnaire. Obesity was defined as a body mass index ≥25 kg/m2. Abdominal obesity (AO) was defined as waist circumference ≥90 cm and 80 cm in males and females, respectively. Dietary nutrient intake was classified based on Korean Dietary Reference Intakes (DRIs). Odds ratios and 95% confidence intervals were calculated after adjusting for age, sex, exercise, smoking, alcohol drinking, total energy consumption, PC1, and PC2. RESULTS: Among the individuals consuming fat (%) above DRI, carriers of Ca binding protein 39 (CAB39)- rs6722579 minor allele (A) have a higher risk of AO than those not carrying the SNP (odds ration [OR] = 3.73, p-value = 2.05e-07; interaction p-value = 1.80e-07). Among the individuals consuming vitamin C above DRI, carriers of carboxypeptidase Q (CPQ)- rs59465035 minor allele (T) have a lower risk of AO than those without that SNP (OR = 0.89, p-value = 1.44e-08; interaction p-value = 9.50e-06). The genetic association with obesity was stronger among individuals with a genetic variant rs4130113 near GHR gene region in those consume folate above DRI and with a genetic variant rs5760920 near CRYBB2 gene region in those consume vitamin B2 above DRI. CONCLUSION: Our study results suggested that interactions of specific polymorphisms at loci and certain nutrients may influence obesity and abdominal obesity.

Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer.

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of ß-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.

Association of a common genetic variant (insertion/deletion) in ACE gene with prostate cancer susceptibility in a Tunisian population.

BACKGROUND: Angiotensin-converting enzyme (ACE) plays a pivotal role in several pathologies including cancers. The association of insertion/deletion (I/D) polymorphism of the ACE gene with prostate cancer (PC) risk remains controversial. We aimed to investigate for the first time, to our Knowledge, in North Africa the potential relationship between ACE I/D polymorphism with PC susceptibility and clinical outcomes of PC patients. METHODS: This case-control study included 143 healthy individuals and 124 patients diagnosed with PC. Using genomic DNA, the samples were genotyped for ACE I/D polymorphism by polymerase chain reaction (PCR). RESULTS: We found that The D allele is significantly associated with an increased risk of PC and D/D + D/I genotypes were at 3 times increased risk of PC ([p = 0.005], OR = 2.95, IC 95% = 1.26-7.09) compared with I/I genotype (p = 0.003, OR = 0.3, IC 95% = 0.12-0.74). We observed an association between D/D and D/I genotypes with advanced age (≥70 years) (p = 0.014; r2  = 0.22). Furthermore, there is a significant prediction of advanced Gleason score ≥8 based on epidemiological parameters and ACE genotype (p = 0.000; R2  = 0.349), although no significant association was observed with stage and metastasis. CONCLUSION: The ACE I/D polymorphism is likely to predispose to PC and could play a role in PC progression and aggressiveness.

Genome-wide association of individual vulnerability with alcohol-associated liver disease: A Korean genome and epidemiology study.

BACKGROUND AND AIMS: The quantity of alcohol leading to alcohol-associated liver disease (ALD) varies individually. Genetic backgrounds contributing to the divergence in individual susceptibility to alcohol-induced liver damage have not been elucidated in detail. APPROACH AND RESULTS: Based on the Korean Genome and Epidemiology Study Health Examination (KoGES_HEXA) cohort data, 21,919 participants (40-79 years old) were included and divided into cases and controls based on the ALD diagnostic criteria proposed by the American College of Gastroenterology. Data generated by a genome wide-association study were analyzed using logistic regression to assess the risk of ALD development in nondrinkers, light drinkers, and heavy drinkers. We detected three loci, gamma-glutamyltransferase 1 (GGT1), zinc protein finger 827 (ZNF827) and HNF1 homeobox A (HNF1A), which were significantly associated with ALD risk. The GGT1 rs2006227 minor allele was strongly associated with all groups. Among the minor alleles of single nucleotide polymorphisms (SNPs) in HNF1A, rs1183910 had the strongest association with a protective effect from ALD in light drinkers. However, this association was not observed in heavy drinkers. Five SNPs on chromosome 11 showed suggestive significance in protective effects against ALD. CONCLUSIONS: SNPs, including HNF1A rs1183910 minor allele, are the most promising genetic candidates for protection against ALD. The expression of genes contributing to ALD development may be altered by the amount of alcohol consumed.

Estimating the influence of body mass index (BMI) on mortality using offspring BMI as an instrumental variable.

OBJECTIVE: High body mass index (BMI) is an important predictor of mortality but estimating underlying causality is hampered by confounding and pre-existing disease. Here, we use information from the offspring to approximate parental BMIs, with an aim to avoid biased estimation of mortality risk caused by reverse causality. METHODS: The analyses were based on information on 9674 offspring-mother and 9096 offspring-father pairs obtained from the 1958 British birth cohort. Parental BMI-mortality associations were analysed using conventional methods and using offspring BMI as a proxy, or instrument, for their parents' BMI. RESULTS: In the conventional analysis, associations between parental BMI and all-cause mortality were U-shaped (Pcurvature < 0.001), while offspring BMI had linear associations with parental mortality (Ptrend < 0.001, Pcurvature > 0.46). Curvature was particularly pronounced for mortality from respiratory diseases and from lung cancer. Instrumental variable analyses suggested a positive association between BMI and mortality from all causes [mothers: HR per SD of BMI 1.43 (95% CI 1.21-1.69), fathers: HR 1.17 (1.00-1.36)] and from coronary heart disease [mothers: HR 1.65 (1.15-2.36), fathers: HR 1.51 (1.17-1.97)]. These were larger than HR from the equivalent conventional analyses, despite some attenuation by adjustment for social indicators and smoking. CONCLUSIONS: Analyses using offspring BMI as a proxy for parental BMI suggest that the apparent adverse consequences of low BMI are considerably overestimated and adverse consequences of overweight are underestimated in conventional epidemiological studies.

The genetics of testosterone contributes to "femaleness/maleness" of cardiometabolic traits and type 2 diabetes.

The genetic architecture of testosterone is highly distinct between sexes. Moreover, obesity is associated with higher testosterone in females but lower testosterone in males. Here, we ask whether male-specific testosterone variants are associated with a male pattern of obesity and type 2 diabetes (T2D) in females, and vice versa. In the UK Biobank, we conducted sex-specific genome-wide association studies and computed polygenic scores for total (PGSTT) and bioavailable testosterone (PGSBT). We tested sex-congruent and sex-incongruent associations between sex-specific PGSTs and metabolic traits, as well as T2D diagnosis. Female-specific PGSBT was associated with an elevated cardiometabolic risk and probability of T2D, in both sexes. Male-specific PGSTT was associated with traits conferring a lower cardiometabolic risk and probability of T2D, in both sexes. We demonstrate the value in considering polygenic testosterone as sex-related continuous traits, in each sex.

IL-6 and IL-10 gene polymorphisms and cirrhosis of liver risk from a comprehensive analysis.

BACKGROUND: Different inflammatory and immune cytokines play a key role in the development of cirrhosis of liver (CL). To investigate the association between interleukin-6,10 (IL-6,10) genes polymorphisms and CL risk through comparison of the allele and genotype distribution frequencies by meta-analysis. METHODS: A literature search covered with the PubMed, Embase, Cochrane Library, Web of Science, Google Scholar, SinoMed (CNKI and Wanfang) through 20th April, 2021. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations. RESULTS: After a comprehensive search, three common polymorphisms (rs1800872, rs1800871, rs1800896) in IL-10 gene were selected, and three common polymorphisms (rs1800795, rs1800796, rs1800797) in IL-6 gene were also identified. The important finding was that IL-10 rs1800872 was a risk factor for CL development. For example, there has a significantly increased relationship between rs1800872 polymorphism and CL both in the whole group (OR: 1.30, 95%CI: 1.01-1.67 in heterozygote model), Asian population (OR: 1.40, 95%CI: 1.03-1.88 in heterozygote model) and hospital-based source of control (OR: 1.40, 95%CI: 1.01-1.96 in dominant model). In addition, significant association was found between rs1800896 and primary biliary cirrhosis subtype disease (OR: 1.30, 95%CI: 1.01-1.68 in allelic contrast model). No association was observed in all three polymorphisms in IL-6 gene. CONCLUSION: Our present study suggests that the IL-10 rs1800872 and rs1800896 polymorphisms is potentially associated with the risk of CL susceptibility.

Genetic and environmental influences on the progression from alcohol use disorder to alcohol-related medical conditions.

BACKGROUND: Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined. METHODS: Using data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data. RESULTS: We identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance. CONCLUSIONS: A moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.

Identification of Genetic Risk Factors for Familial Urinary Bladder Cancer: An Exome Sequencing Study.

PURPOSE: Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete. MATERIALS AND METHODS: We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases. RESULTS: In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair (MLH1 and MSH2) and cellular metabolism (IDH1 and ME1). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls (P = .003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis (P = .001). In addition, a pathogenic variant in CHEK2 (NM_007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant. CONCLUSION: These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology.