Genetic Liability Research Articles

Polygenic Risk Scores and Twin Concordance for Schizophrenia and Bipolar Disorder

Schizophrenia and bipolar disorder are highly heritable psychiatric disorders with strong genetic and phenotypic overlap. Twin and molecular methods can be leveraged to predict the shared genetic liability to these disorders. To investigate whether twin concordance for psychosis depends on the level of polygenic risk score (PRS) for psychosis and zygosity and compare PRS from cases and controls from several large samples and estimate the twin heritability of psychosis. In this case-control study, psychosis PRS were generated from a genome-wide association study (GWAS) combining schizophrenia and bipolar disorder into a single psychosis phenotype and compared between cases and controls from the Schizophrenia and Bipolar Twin Study in Sweden (STAR) project. Further tests were conducted to ascertain if twin concordance for psychosis depended on the mean PRS for psychosis. Structural equation modeling was used to estimate heritability. This study constituted an analysis of existing clinical and population datasets with genotype and/or twin data. Included were twins from the STAR cohort and from the Swedish Twin Registry. Data were collected during the 2006 to 2013 period and analyzed from March 2023 to June 2024. PRS for psychosis based on the most recent GWAS of combined schizophrenia/bipolar disorder. Psychosis case status was assessed by clinical interviews and/or Swedish National Register data. The final cohort comprised 87 pairs of twins with 1 or both affected and 59 unaffected pairs from the STAR project (for a total of 292 twins) as well as 443 pairs with 1 or both affected and 20 913 unaffected pairs from the Swedish Twin Registry. Among the 292 twins (mean [SD] birth year, 1960 [10.8] years; 158 female [54.1%]; 134 male [45.9%]), 134 were monozygotic twins, and 158 were dyzygotic twins. PRS for psychosis was higher in cases than in controls and associated with twin concordance for psychosis (1-SD increase in PRS, odds ratio [OR], 2.12; 95% CI, 1.23-3.87 on case status in monozygotic twins and OR, 2.74; 95% CI, 1.56-5.30 in dizygotic twins). The association between PRS for psychosis and concordance was not modified by zygosity. The twin heritability was estimated at 0.73 (95% CI, 0.30-1.00), which overlapped with the estimate in the full Swedish Twin Registry (0.69; 95% CI, 0.43-0.85). In this case-control study, using the natural experiment of twins, results suggest that twins with greater inherited liability for psychosis were more likely to have an affected co-twin. Results from twin and molecular designs largely aligned. Even as illness vulnerability is not solely genetic, PRS carried predictive power for psychosis even in a modest sample size.

Testing for a causal role of thyroid hormone measurements within the normal range on human metabolism and diseases: a systematic Mendelian randomization

Variation in thyroid function parameters within the normal range has been observationally associated with adverse health outcomes. Whether those associations reflect causal effects is largely unknown. We systematically tested associations between genetic differences in thyrotropin (TSH) and free thyroxine (FT4) within the normal range and more than 1100 diseases and more than 6000 molecular traits (metabolites and proteins) in three large population-based cohorts. This was performed by combining individual and summary level genetic data and using polygenic scores and Mendelian randomization (MR) methods. We performed a phenome-wide MR study in the OpenGWAS database covering thousands of complex phenotypes and diseases. Genetically predicted TSH or FT4 levels within the normal range were predominately associated with thyroid-related outcomes, like goitre. The few extra-thyroidal outcomes that were found to be associated with genetic liability towards high but normal TSH levels included atrial fibrillation (odds ratio=0.92, p-value=2.13×10-3), thyroid cancer (odds ratio=0.57, p-value=2.97×10-4), and specific biomarkers, such as sex hormone binding globulin (β=-0.046, p-value=1.33×10-6) and total cholesterol (β=0.027, p-value=5.80×10-3). In contrast to previous studies that have described the association with thyroid hormone levels and disease outcomes, our genetic approach finds little evidence of an association between genetic differences in thyroid function within the normal range and non-thyroidal phenotypes. The association described in previous studies may be explained by reverse causation and confounding. This research was funded by the Swiss National Science Foundation (P1BEP3_200041). The Fenland study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1, MC_PC_13046 and MC_UU_00006/1). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1, MC_PC_13048 and MC_UU_00006/1).

Genetic liability to human serum metabolites is causally linked to telomere length: insights from genome-wide Mendelian randomization and metabolic pathways analysis.

Telomere has been recognized as a biomarker of accelerating aging, and telomere length (TL) shortening is closely related to diverse chronic illnesses. Human serum metabolites have demonstrated close correlations with TL maintenance or shortening in observational studies. Nevertheless, little is known about the underlying pathological mechanisms, and Mendelian randomization (MR) analysis of serum metabolites may provide a more comprehensive understanding of the potential biological process. We employed a two-sample MR analysis method to assess the causal links between 486 serum metabolites and TL. We applied the inverse-variance weighted (IVW) approach as our primary analysis, and to assure the stability and robustness of our results, additional analysis methods including the weighted median, MR-Egger, and weighted mode were conducted. MR-Egger intercept test was utilized to detect the pleiotropy. Cochran's Q test was implemented to quantify the extent of heterogeneity. Furthermore, the pathway analysis was conducted to identify potential metabolic pathways. We identified 11 known blood metabolites associated with TL. Among these metabolites, four were lipid (taurocholate, dodecanedioate, 5,8-tetradecadienoate, and 15-methylpalmitate), one amino acid (levulinate (4-oxovaleate)), one carbohydrate (lactate), one nucleotide (pseudouridine), one energy (phosphate), and three xenobiotics (2-hydroxyacetaminophen sulfate, paraxanthine, and ergothioneine). The known protective metabolites included levulinate (4-oxovaleate), dodecanedioate, 5,8-tetradecadienoate, lactate, phosphate, paraxanthine, and ergothioneine. Multiple metabolic pathways have been identified as being implicated in the maintenance of telomere length. Our MR analysis provided suggestive evidence supporting the causal relationships between 11 identified blood metabolites and TL, necessitating further exploration to clarify the mechanisms by which these serum metabolites and metabolic pathways may affect the progression of telomeres.

Smoking behaviors, physical activities, pulmonary diseases and COVID-19 severity: A Mendelian randomization study.

Smoking behaviors, physical activities, and pulmonary diseases have been revealed to be associated with COVID-19 severity through observational research. The possible causative effect remains undetermined. To investigate this, we thus carried out a Mendelian randomization (MR) analysis. We chose genetic variants from genome-wide association studies that are strongly linked to 5 exposures related to smoking, 1 exposure related to drinking, 3 levels of physical activity, and 3 pulmonary diseases. The COVID-19 Host Genetics Initiative provided summary-level data for severe COVID-19 (13,769 cases and 1,072,442 noncases), hospitalized COVID-19 (32,519 cases and 2,062,805 noncases), and COVID-19 susceptibility (122,616 cases and 2,475,240 noncases). Univariate and multivariate MR analyses were carried out. Significant associations were found between severe COVID-19 and cigarette smoking per day (OR = 1.357, 95% CI: 1.087-1.694), lifetime smoking index (OR = 2.277, 95% CI: 1.602-3.325), and interstitial lung disease (OR = 1.23, 95% CI: 1.112-1.362), hospitalized COVID-19 and lifetime smoking index (OR = 2.199, 95% CI: 1.738-2.781), smoking initiation (OR = 1.419, 95% CI: 1.230-1.637), and interstitial lung disease (OR = 1.146, 95% CI: 1.082-1.214), as well as COVID-19 susceptibility and lifetime smoking index (OR = 1.39, 95% CI: 1.252-1.543), smoking initiation (OR = 1.235, 95% CI: 1.163-1.311), and duration of vigorous activity per day (OR = 0.733, 95% CI: 0.574-0.935). Duration of vigorous activity per day was suggestively inversely linked to hospitalized COVID-19 (OR = 0.434, 95% CI: 0.221-0.853) and severe COVID-19 (OR = 0.323, 95% CI: 0.123-0.850). The association for lifetime smoking index remained consistent with severe COVID-19, hospitalized COVID-19, and COVID-19 susceptibility in multivariable MR analysis. Genetic liability to lifetime smoking index mediated the interstitial lung disease effects on severe COVID-19 risk (21.0%) and hospitalized COVID-19 risk (14.4%). This study identified several smoking behaviors, duration of vigorous activity per day, and interstitial lung disease that may be causally related to COVID-19 severity.

Associations Between Genetic Risk, Physical Activities, and Distressing Psychotic-like Experiences.

Persistent distressing psychotic-like experiences (PLE) are associated with impaired functioning and future psychopathology. Prior research suggests that physical activities may be protective against psychopathology. However, it is unclear whether physical activities may interact with genetics in the development of psychosis. This study included 4679 participants of European ancestry from the Adolescent Brain Cognitive Development Study. Persistent distressing PLE was derived from the Prodromal-Questionnaire-Brief Child Version using four years of data. Generalized linear mixed models tested the association between polygenic risk score for schizophrenia (PRS-SCZ), physical activities, and PLE. The models adjusted for age, sex, parental education, income-to-needs ratio, family history of psychosis, body mass index, puberty status, principal components for PRS-SCZ, study site, and family. PRS-SCZ was associated with a greater risk for persistent distressing PLE (adjusted relative risk ratio (RRR) = 1.14, 95% CI [1.04, 1.24], P = .003). Physical activity was associated with less risk for persistent distressing PLE (adjusted RRR = 0.87, 95% CI [0.79, 0.96], P = .008). Moreover, physical activities moderated the association between PRS-SCZ and persistent distressing PLE (adjusted RRR = 0.89, 95% CI [0.81, 0.98], P = .015), such that the association was weaker as participants had greater participation in physical activities. These findings demonstrate that the interaction between genetic liability and physical activities is associated with trajectories of distressing PLE. Further research is needed to understand the mechanisms of physical activities and genetic liability for schizophrenia in the development of psychosis.

Assessment of the causal relationship between inflammatory bowel diseases and chronic kidney diseases: A two-sample bidirectional mendelian randomization study among European population.

Kidney function can be impaired in patients with inflammatory bowel diseases (IBD), including Crohn's diseases (CD) and ulcerative colitis (UC). However, the causal relationship between IBD and chronic kidney diseases (CKD) remains unclear. We determined the causal association between IBD and CKD by performing two-sample bidirectional mendelian randomization (MR) analyses. Independent genetic variants were selected as instrumental variables (IVs) of the exposure from open-access genome-wide association studies (GWAS) among European ancestry. IVs-outcome estimates were extracted from three separate GWAS for IBD and two for CKD, respectively. Inverse-variance-weighted model was used as the primary MR method. The pleiotropic effect and heterogeneity were evaluated. For either direction, analyses were performed per outcome database and were subsequently meta-analysed. Genetically predicted IBD was associated with higher risk of CKD (OR: 1.045, 95% CI: 1.016-1.073, P = 0.002) by including 42 344 IBD cases and 229 164 controls. Further analyses showed genetic liability to CD increased the risk of CKD (OR: 1.057, 95% CI: 1.027-1.087, p < 0.001) whereas UC did not (OR: 0.999, 95% CI:0.969-1.031, p = 0.970). In contrast, genetically predicted CKD was not associated with IBD (OR: 1.010, 95% CI: 0.965-1.056, p = 0.676), UC (OR: 1.011, 95% CI: 0.948-1.078, p = 0.746) and CD (OR: 1.024; 95% CI: 0.963-1.089, p = 0.447). We concluded that CD, but not UC, can increase the risk of CKD causally. CD, but not UC, can increase the risk of chronic kidney disease causally. These findings enhance our understanding of the differential impact of IBD subtypes on CKD. It may be necessary to monitor kidney function regularly in patients with CD.

Association of Body Mass Index and Parkinson Disease: A Bidirectional Mendelian Randomization Study.

The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

Association of healthy lifestyle factors and genetic liability with bipolar disorder: Findings from the UK Biobank

BackgroundThe interplay between genetic and lifestyle factors in the development of bipolar disorder (BD) remains unclear. MethodsA cohort study was carried out on 365,517 participants from the UK Biobank. Lifestyle scores, based on smoking, physical activity, diet, alcohol consumption, sedentary behavior, sleep duration, and social contact, were grouped as favorable (scores 6–7), intermediate (scores 4–5), or unfavorable (scores 0–3). The BD polygenic risk score (PRS) was also categorized into high, intermediate, and low-risk groups using PRS tertiles. Cox regression models determined hazard ratios (HRs) and 95 % confidence intervals (CIs) for BD. ResultsDuring the 12.9-year follow-up, 529 individuals developed BD. Comparing those with favorable lifestyles to those with unfavorable participants, the HR of developing BD was 3.28 (95 % CI, 2.76–3.89). Similarly, individuals with a high PRS had a risk of 3.20 (95 % CI, 2.83–3.63) compared to those with a low PRS. Notably, individuals with both a high PRS and an unfavorable lifestyle had a significantly higher risk of BD (HR = 6.31, 95 % CI, 4.14–9.63) compared to those with a low PRS and a favorable lifestyle. Additionally, the interaction between PRS and lifestyle contributed an additional risk, with a relative excess risk of 1.74 (95 % CI, 0.40–3.07) and an attributable proportion due to the interaction of 0.37 (95 % CI, 0.16–0.58). ConclusionsOur findings suggest that genetic liability for BD, measured as PRS, and lifestyle have an additive effect on the risk of developing BD. A favorable lifestyle was associated with a reduced risk of developing BD.

Shared Genetic Liability across Systems of Psychiatric and Physical Illness.

Epidemiological literature has shown that there are extensive comorbidity patterns between psychiatric and physical illness. However, our understanding of the multivariate systems of relationships underlying these patterns is poorly understood. Using Genomic SEM and Genomic E-SEM, an extension for genomic exploratory factor analysis that we introduce and validate, we evaluate the extent to which latent genomic factors from eight domains, encompassing 76 physical outcomes across 1.9 million cases, evince genetic overlap with previously identified psychiatric factors. We find that internalizing, neurodevelopmental, and substance use factors are broadly associated with increased genetic risk sharing across all physical illness domains. Conversely, we find that a compulsive factor is protective against circulatory and metabolic illness, whereas genetic risk sharing between physical illness factors and psychotic/thought disorders was limited. Our results reveal pervasive risk sharing between specific groups of psychiatric and physical conditions and call into question the bifurcation of psychiatric and physical conditions.

Monozygotic twins discordant for depression: An extended network comparison of depressive symptoms, cognitive functions and daily activities

Monozygotic twins share the same genotype; however, they can be phenotypically discordant on various traits. Studying discordant monozygotic twins allows the investigation of differences in associations between symptoms and psychopathological risk factors, controlled for shared genetic liability. The network approach to psychopathology suggests that depressive symptoms, along with risk and protective factors (e.g., cognition, daily activities), form a complex system of mutually interacting components. We compared monozygotic twins discordant for lifetime depression on their respective extended networks of depressive symptoms, cognitive functions and daily activities (intellectual, physical, social), and evaluated if these networks differ in their associations between variables and in the role of each variable within the network. Regularized partial correlations investigated the networks' composition in 147 monozygotic twin pairs discordant for depression from the Danish Twin Registry. Affected twins had stronger overall associations within their network of depressive symptoms, cognitive functions and daily activities than their unaffected co-twins, while the importance of the network components’ associations did not differ between the co-twins. In affected twins, decreased frequency in experiencing happiness had the strongest association with remaining variables (i.e., the most influence in activating other network elements). Also, variables from different groups were significantly associated (e.g., loneliness with delayed memory, pessimism with low social activities, verbal learning with intellectual activities). In unaffected twins, both mood symptoms and cognitive functions were important, but between-groups associations were quasi-absent. These results suggest that external events affecting the ability to feel happiness likely trigger the psychopathological process (depression network activation), independently from the genetic predisposition to depression.

Sex differences in risk factor relationships with subarachnoid haemorrhage and intracranial aneurysms: A Mendelian randomization study.

The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. We conducted a sex-specific two-sample Mendelian randomization study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e. aSAH and unruptured IA combined) as outcomes. We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (p-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (p-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (p-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.

Association between prescription opioid use and heart failure: Cohort studies and Mendelian randomization analysis

BackgroundPrescription opioid use (POU) has been shown to lead to cardiovascular disease (CVD), but its association with heart failure has not been well studied. We investigated the potential causal association between POU and HF using cohort studies and Mendelian Randomization (MR) analysis. MethodsInitially, we examined the longitudinal association between POU and HF using the data from the Health and Retirement Study (HRS) and the UK biobank. Next, we employed a two-sample MR analysis using summary statistics from genome-wide association studies (GWAS) to assess the potential causal associations between POU and HF. ResultsDuring a median of 3.8 and 13.8 years of follow-up, there were 441(8.04 per 1000 person-year) and 16,170 (3.96 per 1000 person-year) HF cases in the HRS and the UK biobank, respectively. After adjusting for covariates, participants who used prescription opioids had a 32% increased risk of developing HF, compared with non-users (HR = 1.32, 95%CI: 1.26–1.38, P < 0.001). In the MR analysis, summary statistics for POU were obtained from 78,808 UK Biobank study participants, and summary data for HF were obtained from 218,792 participants of a European population. A causal effect of genetic liability for POU on an increased risk of HF (OR = 1.16, 95% CI = 1.06, 1.27, P = 0.001) was suggested. The results were generally consistent in the sensitivity analysis, and no pleiotropy or heterogeneity were observed. ConclusionsPOU is associated with a high risk of HF. Our findings provide new insight into prescription opioid use among populations at risk of heart failure. More studies are needed to validate our results and further investigate the underlying mechanisms.

The Genetic Architecture of the Human Corpus Callosum and its Subregions.

The corpus callosum (CC) is the largest set of white matter fibers connecting the two hemispheres of the brain. In humans, it is essential for coordinating sensorimotor responses, performing associative/executive functions, and representing information in multiple dimensions. Understanding which genetic variants underpin corpus callosum morphometry, and their shared influence on cortical structure and susceptibility to neuropsychiatric disorders, can provide molecular insights into the CC's role in mediating cortical development and its contribution to neuropsychiatric disease. To characterize the morphometry of the midsagittal corpus callosum, we developed a publicly available artificial intelligence based tool to extract, parcellate, and calculate its total and regional area and thickness. Using the UK Biobank (UKB) and the Adolescent Brain Cognitive Development study (ABCD), we extracted measures of midsagittal corpus callosum morphometry and performed a genome-wide association study (GWAS) meta-analysis of European participants (combined N = 46,685). We then examined evidence for generalization to the non-European participants of the UKB and ABCD cohorts (combined N = 7,040). Post-GWAS analyses implicate prenatal intracellular organization and cell growth patterns, and high heritability in regions of open chromatin, suggesting transcriptional activity regulation in early development. Results suggest programmed cell death mediated by the immune system drives the thinning of the posterior body and isthmus. Global and local genetic overlap, along with causal genetic liability, between the corpus callosum, cerebral cortex, and neuropsychiatric disorders such as attention-deficit/hyperactivity and bipolar disorders were identified. These results provide insight into variability of corpus callosum development, its genetic influence on the cerebral cortex, and biological mechanisms related to neuropsychiatric dysfunction.

Application of polygenic scores to a deeply phenotyped sample enriched for substance use disorders reveals extensive pleiotropy with psychiatric and somatic traits

Co-occurring psychiatric, medical, and substance use disorders (SUDs) are common, but the complex pathways leading to such comorbidities are poorly understood. A greater understanding of genetic influences on this phenomenon could inform precision medicine efforts. We used the Yale-Penn dataset, a cross-sectional sample enriched for individuals with SUDs, to examine pleiotropic effects of genetic liability for psychiatric and somatic traits. Participants completed an in-depth interview that provides information on demographics, environment, medical illnesses, and psychiatric and SUDs. Polygenic scores (PGS) for psychiatric disorders and somatic traits were calculated in European-ancestry (EUR; n = 5691) participants and, when discovery datasets were available, for African-ancestry (AFR; n = 4918) participants. Phenome-wide association studies (PheWAS) were then conducted. In AFR participants, the only PGS with significant associations was bipolar disorder (BD), all of which were with substance use phenotypes. In EUR participants, PGS for major depressive disorder (MDD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), schizophrenia (SCZ), body mass index (BMI), coronary artery disease (CAD), and type 2 diabetes (T2D) all showed significant associations, the majority of which were with phenotypes in the substance use categories. For instance, PGSMDD was associated with over 200 phenotypes, 15 of which were depression-related (e.g., depression criterion count), 55 of which were other psychiatric phenotypes, and 126 of which were substance use phenotypes; and PGSBMI was associated with 138 phenotypes, 105 of which were substance related. Genetic liability for psychiatric and somatic traits is associated with numerous phenotypes across multiple categories, indicative of the broad genetic liability of these traits.

Genetic predisposition to type 2 diabetes mellitus and aortic dissection: a Mendelian randomisation study.

This Mendelian randomization (MR) study aimed to explore the causal relationship between the genetic predisposition to type 2 diabetes mellitus (T2DM) and aortic dissection (AD), and to assess associations with genetically predicted glycemic traits. The study sought to verify the inverse relationship between T2DM and AD using a more robust and unbiased method, building on the observational studies previously established. The study employed a two-sample and multivariable MR approach to analyze genetic data from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) with 74,124 cases and 824,006 controls, and the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) involving up to 196,991 individuals. For AD data, FinnGen Release 10 was used, including 967 cases and 381,977 controls. The research focused on three foundational MR assumptions and controlled for confounders like hypertension. Genetic instruments were selected for their genome-wide significance, and multiple MR methods and sensitivity analyses were conducted. The study revealed no significant effect of genetic predisposition to T2DM on the risk of AD. Even after adjusting for potential confounders, the results were consistent, indicating no causal relationship. Additionally, glycemic traits such as fasting glucose, fasting insulin, and HbA1c levels did not show a significant impact on AD susceptibility. The findings remained stable across various MR models and sensitivity analyses. In contrast, genetic liability to T2DM and glycemic traits showed a significant association with coronary artery disease (CAD), aligning with the established understanding. Contrary to previous observational studies, this study concludes that genetic predisposition to T2DM does not confer protection against AD. These findings underscore the imperative for further research, particularly in exploring the preventative potential of T2DM treatments against AD and to facilitate the development of novel therapeutic interventions.

Causal effects of denture wearing on epigenetic age acceleration and the mediating pathways: a mendelian randomization study

BackgroundThe epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators.MethodsUsing summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy.ResultsUnivariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (β: 2.47, 95% CI: 0.93–4.01, p = 0.002), PhenoAA (β: 3.00, 95% CI: 1.15–4.85, p = 0.001), and HannumAA (β: 1.96, 95% CI: 0.58–3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05).ConclusionsOur findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

Genetic predisposition to milder forms of COVID-19 may provide some resilience to head and neck cancers.

The impact of the COVID-19 pandemic on head and neck cancer (HNC) has been suggested, but the causal relationship remains unclear. We explore this connection by utilizing the Mendelian randomization (MR) approach applied to publicly available genome-wide association study (GWAS) summary datasets for COVID-19 and HNC. The datasets included critical COVID-19 (13,769 cases, 1,072,442 controls), hospitalized COVID-19 (32,519 cases, 2,062,805 controls), SARS-CoV-2 infection (122,616 cases, 2,475,240 controls), and HNC (2,131 cases, 287,137 controls). Mechanistic underpinnings of the causal relationships identified by MR analysis were explored through functional annotation augmented by AI-based literature data mining. Surprisingly, a genetic predisposition to contracting a milder form of COVID-19 substantially reduced the risks of developing HNC (OR: 0.52, 95% CI: 0.35-0.78, p = 1.42E-03), with no significant association between genetic liability to severe COVID-19 and the risk of HNC detected. Additionally, our findings highlighted 14 genes linked to SARS-CoV-2 infection, potentially playing a protective role in the context of HNC. These genes include OAS1, LOC107985887, BCL11A, DPP9, LOC107984685, LINC02326, MUC4, NXPE3, IFNAR2, LZTFL1, LOC105372437, NAPSA, LOC105376622, LOC107986082, and SLC6A20. Our study emphasizes the protective role of the genetic liability to milder COVID-19 in reducing the risk of HNC while refuting a causal relationship between severe COVID-19 and HNC.

Genomic insights into the shared and distinct genetic architecture of cognitive function and schizophrenia

Cognitive impairment is a major determinant of functional outcomes in schizophrenia, however, understanding of the biological mechanisms underpinning cognitive dysfunction in the disorder remains incomplete. Here, we apply Genomic Structural Equation Modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank. We identified three broad factors that underly the genetic correlations between the cognitive tests. We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). Global genetic correlations showed a significant moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found substantial polygenic overlap between each cognitive factor and schizophrenia and biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we show that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptoms in the Norwegian Thematically Organized Psychosis cohort. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.

Polygenic risk score for blood pressure and lifestyle factors with overall and CVD mortality: a prospective cohort study in a Japanese population.

Although previous polygenic risk score (PRS) studies for cardiovascular disease (CVD) focused on incidence, few studies addressed CVD mortality and quantified risks by environmental exposures in different genetic liability groups. This prospective study aimed to examine the associations of blood pressure PRS with all-cause and CVD mortality and to quantify the attributable risk by modifiable lifestyles across different PRS strata. 9,296 participants in the Japan Multi-Institutional Collaborative Cohort Study without hypertension at baseline were analyzed in this analysis. PRS for systolic blood pressure and diastolic blood pressure (PRSSBP and PRSDBP) were developed using publicly available Biobank Japan GWAS summary statistics. CVD-related mortality was defined by the International Classification of Diseases 10th version (I00-I99). Cox-proportional hazard model was used to examine associations of PRSs and lifestyle variables (smoking, drinking, and dietary sodium intake) with mortality. During a median 12.6-year follow-up period, we observed 273 all-cause and 41 CVD mortality cases. Compared to the middle PRS group (20-80th percentile), adjusted hazard ratios for CVD mortality at the top PRS group ( > 90th percentile) were 3.67 for PRSSBP and 2.92 for PRSDBP. Attributable risks of CVD mortality by modifiable lifestyles were higher in the high PRS group ( > 80th percentile) compared with the low PRS group (0-80th percentile). In summary, blood pressure PRS is associated with CVD mortality in the general Japanese population. Our study implies that integrating PRS with lifestyle could contribute to identify target populations for lifestyle intervention even though improvement of discriminatory ability by PRS alone is limited.

Distinct genetic liability profiles define clinically relevant patient strata across common diseases

Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.