Polygenic Scores Research Articles

8039 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study

Abstract Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None. Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p <0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes. Presentation: 6/2/2024

Multi-ancestry GWAS meta-analyses of lung cancer reveal susceptibility loci and elucidate smoking-independent genetic risk

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 pleiotropic cancer locus in squamous cell lung carcinoma. Overall, we report twelve novel risk loci for overall lung cancer, lung adenocarcinoma, and squamous cell lung carcinoma, nine of which are externally replicated. Finally, we perform PheWAS on polygenic risk scores for lung cancer, with and without conditioning on smoking. The unconditioned lung cancer polygenic risk score is associated with smoking status in controls, illustrating a reduced predictive utility in non-smokers. Additionally, our polygenic risk score demonstrates smoking-independent pleiotropy of lung cancer risk across neoplasms and metabolic traits.

Sex-specific association between schizophrenia polygenic risk and subclinical schizophrenia-related traits

BackgroundAccording to the dimensional view of psychiatric disorders, psychosis is expressed as a continuum in the general population. However, the investigation of the putative genetic aetiological continuity between its clinical and subclinical phenotypes has yielded mixed results. We aimed to replicate previous findings regarding the association of polygenic risk for schizophrenia with subclinical traits (i.e., schizotypy traits and psychotic-like experiences), and to examine the role of sex in this association in a large nonclinical sample. MethodsThe Multidimensional Schizotypy Scale and the Community Assessment of Psychic Experiences were assessed in 919 nonclinical participants. Polygenic Risk Scores for schizophrenia (SZ-PRSs) were computed using the PRS-CS method based on the latest genome-wide association study of schizophrenia. Summary statistics derived from the total GWAS sample and stratified by sex were used. Linear regression analyses tested the associations of the SZ-PRSs with the psychometric variables, both in the total sample and by sex. ResultsNo associations were found between the SZ-PRSs and the positive, negative or disorganized dimensions of schizotypy in the total sample. Likewise, no associations were found with psychotic-like experiences. However, the sex-stratified analyses revealed a male-specific association with positive schizotypy. Similar results were obtained with the PRSs derived from the sex-stratified summary statistics. DiscussionOur results are consistent with the lack of clear evidence of an association between SZ common genetic risk and its subclinical phenotypes. Nevertheless, the male-specific association found suggests that this PRS might explain better the male phenotype, as reported in previous studies. Future studies should put a focus on the role of sex in this association to unravel its sex specificities.

Age, anticoagulants, hypertension and cardiovascular genetic traits predict cranial ischaemic complications in patients with giant cell arteritis

ObjectivesThis project aimed to determine whether cranial ischaemic complications at the presentation of giant cell arteritis (GCA) were associated with pre-existing cardiovascular (CV) risk factors, CV disease or genetic risk...

Novel risk loci for COVID-19 hospitalization among admixed American populations.

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.

Are women's breast cancer risk appraisals in line with updated clinical risk estimates communicated? Results from a UK Family History Risk and Prevention Clinic.

The incorporation of breast density and a polygenic risk score (PRS) into breast cancer risk prediction models can alter previously communicated risk estimates. Previous research finds that risk communication does not usually change personal risk appraisals. This study aimed to examine how women from the Family History Risk (FH-Risk) study appraise their breast cancer risk following communication of an updated risk estimate. In the FH-Risk study 323 women attended a consultation to receive an updated breast cancer risk estimate. A subset (n=190) completed a questionnaire, assessing their subjective breast cancer risk appraisals, satisfaction with the information provided and cancer related worry. One hundred and three were notified of a decrease risk, 34 an increase and 53 an unchanged risk. Women's subjective risk appraisals were in line with the updated risk estimates provided, with age, a PRS and breast density explaining most of the variance in these appraisals. Those notified of an increased risk demonstrated higher subjective risk perceptions compared to those whose risk remained unchanged or decreased. Women's subjective breast cancer risk appraisals are amenable to change following updated risk feedback, with new information breast density and a PRS accepted and integrated into existing risk appraisals. Trust in the service, the analogies and visual communication strategies used may have positively influenced the integration of this new information. Further research is warranted to assess whether similar patterns emerge for other illnesses and in different clinical contexts to determine the best strategies for communicating updated risk estimates.

Dietary habits and genetic susceptibility: correlations between nutritional intake and genetic risks for schizophrenia and bipolar disorder

Dietary habits may impact the prevention and management of schizophrenia (SCZ) and bipolar disorder (BD), and genetic and environmental factors can influence both these habits and these disorders. This study investigated the effects of genetic predispositions to SCZ and BD on current dietary habits among older adults with lifestyle-related diseases, potentially offering insights for preventive mental health strategies. A cohort of 730 older patients who were diagnosed with or suspected of having lifestyle-related diseases was assessed for eight current dietary categories: miso soup, Japanese tea, green and yellow vegetables, light-colored vegetables, fruits, pickles, meats, and soybeans. Polygenic risk scores (PRSs) for the risk of SCZ and BD, including BD types I and II, the shared risk of SCZ and BD, and the differentiation of SCZ from BD, were calculated utilizing data from large-scale genome-wide association studies (GWASs). Our findings revealed that PRSs for SCZ and BD risk significantly influenced specific dietary habits, particularly decreased consumption of nutrient-rich foods such as light-colored vegetables (SCZ, R2 = 0.0096, p = 3.54 × 10−3; BD, R2 = 0.0074, p = 9.09 × 10−3) and soybeans (SCZ, R2 = 0.0061, p = 0.019; BD, R2 = 0.014, p = 8.38 × 10−4). Notable differences in dietary effects were observed between PRSs for BD I and BD II, with a more pronounced impact associated with BD I (e.g., light-colored vegetables, BD I, R2 = 0.015, p = 3.11 × 10−4; BD II, p > 0.05). Moreover, shared genetic factors for SCZ and BD were correlated with lower intakes of miso soup (R2 = 0.013, p = 1.21 × 10−3), Japanese tea (R2 = 0.0092, p = 5.59 × 10−3), light-colored vegetables (R2 = 0.010, p = 2.92 × 10−3), and soybeans (R2 = 0.014, p = 3.13 × 10−4). No significant correlations were found between PRSs for differentiating SCZ from BD and any dietary patterns (p > 6.25 × 10−3). Genetic risks shared by individuals with SCZ and BD may influence dietary choices in older adults, emphasizing the potential for dietary modifications as part of comprehensive strategies for the prevention of the SCZ and BD onset, as well as for the treatment of individuals at risk of or diagnosed with SCZ and BD.

Association of a composite trait for anthropometrics, adiposity and energy expenditure with cardiometabolic diseases: An age-stratified cohort and genetic risk score analysis.

Various anthropometric measures capture distinct as well as overlapping characteristics of an individual's body composition. To characterize independent body composition measures, we aimed to reduce easily-obtainable individual measures reflecting adiposity, anthropometrics and energy expenditure into fewer independent constructs, and to assess their potential sex- and age-specific relation with cardiometabolic diseases. Analyses were performed within European ancestry participants from UK Biobank (N = 418,963, mean age 58.0 years, 56% women). Principal components (PC) analyses were used for the dimension reduction of 11 measures of adiposity, anthropometrics and energy expenditure. PCs were studied in relation to incident type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). Multivariable-adjusted Cox regression analyses, adjusted for confounding factors, were performed in all and stratified by age. Genome-wide association studies were performed in half of the cohort (N = 156,295) to identify genetic variants as instrumental variables. Genetic risk score analyses were performed in the other half of the cohort stratified by age of disease onset (N = 156,295). We identified two PCs, of which PC1 reflected lower overall adiposity (negatively correlated with all adiposity aspects) and PC2 reflected more central adiposity (mainly correlated with higher waist-hip ratio, but with lower total body fat) and increased height, collectively capturing 87.8% of the total variance. Similar to that observed in the multivariable-adjusted regression analyses, we found associations between the PC1 genetic risk score and lower risks of CAD and T2D [CAD cases <50 years, odds ratio: 0.91 (95% confidence interval 0.87, 0.94) per SD; T2D cases <50 years, odds ratio: 0.76 (0.72, 0.81)], which attenuated with higher age (p-values 8.13E-4 and 2.41E-6, respectively). No associations were found for PC2. The consistently observed weaker associations of the composite traits with cardiometabolic disease suggests the need for age-specific cardiometabolic disease prevention strategies.

Development of a polygenic score predicting drug resistance and patient outcome in breast cancer

Gene expression profiles of hundreds of cancer cell-lines and the cell-lines’ response to drug treatment were analyzed to identify genes whose expression correlated with drug resistance. In the GDSC dataset of 809 cancer cell lines, expression of 36 genes were associated with drug resistance (increased IC50) to many anti-cancer drugs. This was validated in the CTRP dataset of 860 cell lines. A polygenic score derived from the correlation coefficients of the 36 genes in cancer cell lines, UAB36, predicted resistance of cell lines to Tamoxifen. Although the 36 genes were selected from cell line behaviors, UAB36 successfully predicted survival of breast cancer patients in three different cohorts of patients treated with Tamoxifen. UAB36 outperforms two existing predictive gene signatures and is a predictor of outcome of breast cancer patients independent of the known clinical co-variates that affect outcome. This approach should provide promising polygenic biomarkers for resistance in many cancer types against specific drugs.

A meta-analysis and polygenic score study identifies novel genetic markers for waist-hip ratio in African populations.

Understanding the genetic underpinnings of anthropometric traits in diverse populations is crucial for gaining insights into their biological mechanisms and potential implications for health. We conducted a genome-wide association study, meta-analysis, and gene set analysis of waist-hip ratio (WHR), WHR adjusted for BMI (WHRadjBMI), waist circumference, BMI, and height using the African Collaborative Center for Microbiome and Genomics Research (ACCME)cohort (n = ~11,000) for discovery and polygenic score target analyses and the Africa America Diabetes Mellitus (AADM) study (n = ~5200) for replication and polygenic score validation. We generated and compared polygenic scores from European, African, Afro-Caribbean, and multiethnic ancestry populations. The top loci associated with each trait in the meta-analysis were in CD36 (rs3211826 [p = 5.90 × 10-12] for WHR and rs73709003 [p = 1.75 × 10-13] for WHRadjBMI), IFI27L1 (rs59775050 [p = 2.66 × 10-08] for waist circumference), INPP4B (rs2636629 [p = 1.44 × 10-09] for BMI), and HMGA1 (rs6937622 [p = 1.40 × 10-15] for height) gene regions. A novel variant rs7797157, near GNAT3, was also significantly associated with WHR (p = 2.50 × 10-10) and WHRadjBMI (p = 2.66 × 10-11). The ancestry-specific parameters for the best predictive polygenic scores were European ancestry (R2 = 0.68%; p = 1.63 × 10-16) and multiethnic ancestry (R2 = 0.06%; p = 1.29 × 10-02) for WHR; European ancestry (R2 = 1.36%; p = 2.94 × 10-31) and multiethnic ancestry (R2 = 1.12%; p = 3.52 × 10-25) for BMI; and European ancestry (R2 = 3.16%; p = 2.95 × 10-73), African ancestry (R2 = 4.16%; p = 1.75 × 10-96), and African and Afro-Caribbean ancestry (R2 = 2.67%; p = 4.35 × 10-62) for height. The discovery of a novel locus for WHR and genetic signals for each trait and the assessment of polygenic score performance underscore the importance of conducting well-powered studies in diverse populations.

Intergenerational and genetic influences on physical activity: family data from the HUNT study, Norway

ObjectivesThe objectives of this study are to examine the association of physical activity in parents with physical activity in their adult offspring and explore if the offspring’s genetic liability (ie,...

Using a Polygenic Risk Score to Improve the Risk Prediction of Non-Small Cell Lung Cancer in Taiwan.

Low-dose computed tomography (LDCT) can help reducing lung cancer mortality. In Taiwan, the existing screening criteria revolve around smoking habits and family history of lung cancer. The role of genetic variation in non-small cell lung cancer (NSCLC) development is increasingly recognized. In this study, we aimed to investigate the potential benefits of polygenic risk scores (PRSs) in predicting NSCLC and enhancing the effectiveness of screening programs. We conducted a retrospective cohort study that included participants without prior diagnosis of lung cancer and later received LDCT for lung cancer screening. Genetic data for these participants were obtained from the project of Taiwan Precision Medicine Initiative. We adopted the model of genome-wide association study-derived PRS calculation using 19 susceptibility loci associated with the risk of NSCLC as reported by Dai et al. We studied a total of 2,287 participants (1,197 male, 1,090 female). More female participants developed NSCLC during the follow-up period (4.4% v 2.5%, P = .015). The only risk factor of NSCLC diagnosis among male participants was age. Among female participants, independent risk factors of NSCLC diagnosis were age (adjusted hazard ratio [aHR], 1.08 [95% CI, 1.04 to 1.11]), a family history of lung cancer (aHR, 3.21 [95% CI, 1.78 to 5.77]), and PRS fourth quartile (aHR, 2.97 [95% CI, 1.25 to 7.07]). We used the receiver operating characteristics to show an AUC value of 0.741 for the conventional model. With the further incorporation of PRS, the AUC rose to 0.778. The evaluation of PRS for NSCLC prediction holds promise for enhancing the effectiveness of lung cancer screening in Taiwan especially in women. By incorporating genetic information, screening criteria can be tailored to identify individuals at higher risks of NSCLC.

Gene-diet interactions in carbonated sugar-sweetened beverage consumption and metabolic syndrome risk: A machine learning analysis in a large hospital-based cohort

Background and aimCarbonated sugar-sweetened beverages (CSSB) intake has been increasingly linked to metabolic diseases. To investigate the association between CSSB intake and metabolic syndrome (MetS) risk, and the interaction between genetic predisposition to CSSB intake and dietary patterns. MethodsWe examined a hospital-based cohort of 57,940 participants, categorized into low-CSSB (n=52,848) and high-CSSB (n=5,092) groups based on a 50 ml daily consumption cutoff. A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) associated with CSSB intake, and SNP-SNP/SNP-environment interactions were explored. Using XGBoost and deep neural network (DNN) approaches, we developed prediction models for CSSB intake. ResultsThe low- and high-CSSB groups daily consumed an average of 0.56 and 8.91 g sugar from the soda, respectively. The high-CSSB group had unhealthy dietary habits and a lower intake of carotenoids, folate, vitamins C and D, calcium, flavonoids, and phenols than the low-CSSB group, consistent with the results of the prediction models. A polygenic risk score (PRS) based on 6 selected SNPs, linked to genes involved in obesity, diabetes, and nervous system disorders, showed the strongest association with CSSB intake and insulin resistance. Notably, carbohydrate, fat, and Western-style diet (WSD) intake interacted with the PRS, with lower carbohydrate and higher fat and WSD intakes associated with a stronger PRS-sugar intake relationship. The prediction models by XGboost and DNN mainly included dietary factors to explain CSSB intake. ConclusionsA significant interplay between genetic predisposition and poor dietary habits, particularly increased CSSB intake associated with WSD, contributed to MetS risk. It suggested that personalized dietary interventions based on genetic profiles could mitigate MetS risk, especially in populations transitioning to Westernized diets.

Association between polygenic risk scores combined with clinical characteristics and antidepressant efficacy

BackgroundWhile millions of people suffer from major depressive disorder (MDD), research has shown that individual differences in antidepressant efficacy exist, potentially attributable to various factors. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response are seldom reported. Here, we examined whether PRSs for MDD and schizophrenia (SCZ) are associated with antidepressant effectiveness and the influence of other factors. MethodsA total of 999 patients were included, and the PRSs for the MDD and SCZ were calculated. The main outcome was a change in the 17-item Hamilton Depression Rating Scale (HAMD17) scores from before to after 2-week treatment. The Mann-Whitney test, Spearman correlation analysis, multiple stepwise linear regression analysis, and interaction analysis were used for statistical analysis. ResultsIn the 912 subjects passing quality control, a difference in the HAM-D17 score reduction rate between the MDD phenotype PRS (MDD-PRS) high-risk and the low-risk groups was discovered (P = 0.009), and a correlation was found between the MDD-PRS and the HAM-D17 score reduction rate (r = −0.075, P = 0.024). Moreover, antidepressant efficacy was related to MDD-PRS (β = −4.086, P = 0.039), the Snaith-Hamilton Pleasure Scale-total score (β = −0.009, P = 0.005), and non-first episode (β = −0.039, P < 0.001). However, the result of the interaction analysis was nonsignificant. LimitationsThe main limitation was that only 1309 targeted genes were selected based on pathways known to be involved in MDD and/or antidepressant effects. ConclusionThese findings suggest a difference in antidepressant efficacy between patients in different MDD-PRS groups. Moreover, the MDD-PRS combined with clinical characteristics partially explained inter-individual differences in antidepressant efficacy.

Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation.

Keratoconus (KC) is a corneal disorder with complex etiology, apparently involving both genetic and environmental factors, characterized by progressive thinning and protrusion of the cornea. We aimed to identify novel genetic regions associated with KC susceptibility, elucidate relevant genes for disease development, and explore the translational implications for therapeutic intervention and risk assessment. We conducted a genome-wide association study (GWAS) that integrated previously published data with newly generated genotyping data from an independent European cohort. To evaluate the clinical translation of our results, we performed functional annotation, gene prioritization, polygenic risk score (PRS), and drug repositioning analyses. We identified two novel genetic loci associated with KC, with rs2806689 and rs807037 emerging as lead variants (P = 1.71E-08, odds ratio [OR] = 0.88; P = 1.93E-08, OR = 1.16, respectively). Most importantly, we identified 315 candidate genes influenced by confirmed KC-associated variants. Among these, MINK1 was found to play a pivotal role in KC pathogenesis through the WNT signaling pathway. Moreover, we developed a PRS model that successfully differentiated KC patients from controls (P = 7.61E-16; area under the curve = 0.713). This model has the potential to identify individuals at high risk for developing KC, which could be instrumental in early diagnosis and management. Additionally, our drug repositioning analysis identified acetylcysteine as a potential treatment option for KC, opening up new avenues for therapeutic intervention. Our study provides valuable insights into the genetic and molecular basis of KC, offering new targets for therapy and highlighting the clinical utility of PRS models in predicting disease risk.

Genetics of suicide ideation. A role for inflammation and neuroplasticity?

Suicide is a leading cause of death worldwide. Suicide ideation (SI) is a known risk factor for suicide behaviour (SB). The current psychobiology and genetic predisposition to SI and SB are poorly defined. Despite convincing relevance of a genetic background for SI, there is no current implementable knowledge about the genetic makeup that identifies subjects at risk for it. One of the possible reasons for the absence of a clear-cut evidence is the polygenetic nature of SI along with the very large sample sizes that are needed to observe significant genetic association result. The CATIE sample was instrumental to the analysis. SI was retrieved as measured by the Calgary test. Clinical possible covariates were identified by a nested regression model. A principal component analysis helped in defining the possible genetic stratification factors. A GWAS analysis, polygenic risk score associated with a random forest analysis and a molecular pathway analysis were undertaken to identify the genetic contribution to SI. As a result, 741 Schizophrenic individuals from the CATIE were available for the genetic analysis, including 166,325 SNPs after quality control and pruning. No GWAS significant result was found. The random forest analysis conducted by combining the polygenic risk score and several clinical variables resulted in a possibly overfitting model (OOB error rate < 1%). The molecular pathway analysis revealed several molecular pathways possibly involved in SI, of which those involved in microglia functioning were of particular interest. A medium-small sample of SKZ individuals was analyzed to shed a light on the genetic of SI. As an expected result from the underpowered sample, no GWAS positive result was retrieved, but the molecular pathway analysis indicated a possible role of microglia and neurodevelopment in SI.

A GWAS for grip strength in cohorts of children-Advantages of analysing young participants for this trait.

Grip strength (GS) is a proxy measure for muscular strength and a predictor for bone fracture risk among other diseases. Previous genome-wide association studies (GWASs) have been conducted in large cohorts of adults focusing on scores collected for the dominant hand, therefore increasing the likelihood of confounding effects by environmental factors. Here, we perform the first GWAS meta-analyses on maximal GS with the dominant (GSD) and non-dominant (GSND) hand in two cohorts of children (ALSPAC, N = 5450; age range = 10.65-13.61; Raine Study, N = 1162, age range: 9.42-12.38 years). We identified a novel significant association for GSND (rs9546244, LINC02465, p = 3.43e-08) and replicated associations previously reported in adults including with a HOXB3 gene marker that shows an expression quantitative trait locus (eQTL) effect. Despite a much smaller sample (~3%) compared with the UK Biobank we replicated correlation analyses previously reported in this much larger adult cohort, such as a negative correlation with coronary artery disease. Although the results from the polygenic risk score (PRS) analyses did not survive multiple testing correction, we observed nominally significant associations between GS and risk of overall fracture, as previously reported, as well ADHD which will require further investigations. Finally, we observed a higher SNP-heritability (24%-41%) compared with previous studies (4%-24%) in adults. Overall, our results suggest that cohorts of children might be better suited for genetic studies of grip strength, possibly due to the shorter exposure to confounding environmental factors compared with adults.

Clinical Utility of Polygenic Risk Scores for Embryo Selection: A Points to Consider Statement of the American College of Medical Genetics and Genomics (ACMG)

(Abstracted from Genet Med 26:101052) Polygenic risk scores (PRSs) quantify the combined associations of multiple single nucleotide variations in an individual’s genome to estimate their likelihood of developing certain diseases based on population data. Although PRS availability for adults is currently limited, it is expected to grow.

Characterization of primary Sjögren's syndrome in the Taiwan Han population through a genome-wide association study and polygenic risk score analysis

BackgroundSjögren's syndrome (SS) is an autoimmune disorder that primarily affects the exocrine glands, leading to dryness of mucous membranes and systemic manifestations. This study aimed to identify genetic markers associated with primary SS (pSS) in the Taiwan Han population through a hospital-based genome-wide association study (GWAS) and polygenic risk score (PRS) analysis, addressing the lack of genetic research. ResultsThis study included 11,390 patients diagnosed with pSS and 113,900 controls. GWAS identified one known locus and eight novel loci. Known HLA alleles, including HLA-DRB1*15:01 and HLA-DQA1*03:01, were successfully replicated in a consistent effect direction. PRS analysis revealed that several autoimmune diseases share similar genetic backgrounds with pSS. ConclusionThis study represents the largest cohort to date on the genetics of pSS in the Taiwan Han population. Our findings provide valuable insights into the pathogenesis of pSS and emphasize the comorbidities associated with it as an autoimmune disease.

Refining criteria for a neurodevelopmental sub-phenotype of bipolar disorders: a FondaMental Advanced Centers of Expertise for Bipolar Disorders study

Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. Neurodevelopmental factors were suggested to contribute to the etiology of BD, yet a specific neurodevelopmental phenotype of the disorder remains unidentified. Our objective was to define and characterize a neurodevelopmental phenotype (NDP) in BD and validate its associations with clinical outcomes, polygenic risk scores (PGS), and treatment responses. We analyzed the FACE-BD cohort of 4,468 BD patients, a validation cohort of 101 BD patients, and two independent replication datasets of 274 and 89 BD patients. Using factor analyses, we identified a set of criteria for defining NDP. We next developed a scoring system for NDP-load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and sex with bootstrap replications. Our study established a NDP in BD consisting of nine clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention deficit hyperactivity disorder (ADHD), early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, specific learning disorders. Patients with higher NDP-load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between the NDP-load and PGS for ADHD suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and ADHD. The proposed NDP constitutes a promising clinical tool for patient stratification in BD.