Individuals Of European Ancestry Research Articles

Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in non-syndromic sagittal and metopic craniosynostosis.

The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23-Glu-Ala17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar etal. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar etal. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001).

Longitudinal method comparison: modeling polygenic risk for post-traumatic stress disorder over time in individuals of African and European ancestry

Longitudinal method comparison: modeling polygenic risk for post-traumatic stress disorder over time in individuals of African and European ancestry

ComorbidPGS: an R package assessing shared predisposition between Phenotypes using Polygenic Scores.

Introduction Polygenic Score (PGS) is a valuable method for assessing the estimated genetic liability to a given outcome or genetic variability contributing to a quantitative trait. While PRSs are widely used for complex traits, their application in uncovering shared genetic predisposition between phenotypes, i.e. when genetic variants influence more than one phenotype, remains limited. Methods We developed an R package, comorbidPGS, which facilitates a systematic evaluation of shared genetic effects among (cor)related phenotypes using PGSs. The comorbidPGS package takes as input a set of Single Nucleotide Polymorphisms (SNPs) along with their established effects on the original phenotype (Po), referred to as Po-PGS. It generates a comprehensive summary of effect(s) of Po-PGS on target phenotype(s) (Pt) with customisable graphical features. Results We applied comorbidPGS to investigate the shared genetic predisposition between phenotypes defining elevated blood pressure (Systolic Blood Pressure, SBP; Diastolic Blood Pressure, DBP; Pulse Pressure, PP) and several cancers (Breast Cancer, BrC; Pancreatic Cancer, PanC; Kidney Cancer, KidC; Prostate Cancer, PrC; Colorectal Cancer, CrC) using the European ancestry UK Biobank individuals and GWAS meta-analyses summary statistics from independent set of European ancestry individuals. We report a significant association between elevated DBP and the genetic risk of PrC (β (SE)=0.066 (0.017), P-value=9.64×10^(-5)), as well as between CrC PGS and both, lower SBP (β (SE)=-0.10 [0.029], P-value=3.83×10^(-4))) and lower DBP (β (SE)=-0.055 [0.017], P-value=1.05×10^(-3)). Our analysis highlights two nominally significant relationships for individuals with genetic predisposition to elevated SBP leading to higher risk of KidC (OR [95%CI]=1.04 [1.0039-1.087], P-value=2.82×10^(-2)) and PrC (OR [95%CI]=1.02 [1.003-1.041], P-value=2.22×10^(-2)). Conclusion Using comorbidPGS, we underscore mechanistic relationships between blood pressure regulation and susceptibility to three comorbid malignancies. This package offers valuable means to evaluate shared genetic susceptibility between (cor)related phenotypes through polygenic scores.

Association Between Family History and Early-Onset Atrial Flutter Across Racial and Ethnic Groups.

Genetic and familial contributions to early-onset atrial fibrillation are described primarily in individuals of European ancestry. However, the role of racial and familial contributions in the pathogenesis of early-onset atrial flutter (EOAFL) is unclear. In this cross-sectional study, participants were enrolled prospectively from 2015 to 2021 in multiple academic centers with a diagnosis of atrial flutter (AFL) confirmed by ECG. EOAFL was defined as a diagnosis of AFL before age 66 years with no concomitant or previous diagnosis of atrial tachyarrhythmias. Family history was adjudicated through baseline questionnaires and direct family interviews about the diagnosis of atrial tachyarrhythmias, stroke, and cardiomyopathy. The primary exposure was a positive family history in first-degree relatives, and the primary outcome was the odds of EOAFL versus late-onset AFL. A total of 909 patients were enrolled. Participants with a positive family history of atrial tachyarrhythmias were younger, less likely to be of Black race, and more likely to have EOAFL. The adjusted odds ratio (OR) for EOAFL in those with a positive family history was 1.8 (95% CI, 1.1-3.0). There was an increased odds of EOAFL in those of Black race (OR, 2.1 [95% CI, 1.4-3.2]), alcohol use (OR, 1.6 [95% CI, 1.0-2.6]), and obstructive sleep apnea (OR, 1.9 [95% CI, 1.0-3.4]). Use of cardioselective β blockers or calcium channel blockers before the diagnosis of AFL were associated with a lower odds of EOAFL (OR, 0.5 [95% CI, 0.2-0.9]). These findings suggest a potentially hereditary predisposition to EOAFL across race and ethnicity, warranting further study of the genetic contributions to AFL.

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis.

Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Abstract PO2-08-03: Developing a polygenic risk score for precision prevention of estrogen receptor-positive (ER+)/HER2- breast cancer in Brazilian women

Abstract Polygenic risk scores (PRS) quantify the genetic risk of diseases based on risk alleles in genomic loci identified in genome-wide association studies (GWAS). As individuals of European ancestry are overrepresented in GWAS, PRS performance may vary in individuals of different ancestries. Brazil is the largest and most populated country in Latin America, with around 43% of admixed individuals, and data on breast cancer PRS performance for this population is lacking. We aimed to evaluate the performance of a breast cancer PRS with 313 SNPs generated with Europeans in Brazilian population. In this case-control study, we expect to include 1000 women age >= 18 years old with current or previous diagnosis of ER+/HER2- breast cancer. Germline DNA samples are genotyped with Illumina Infinium Global Screening Array-24 v3.0 chip. Controls are healthy woman previously genotyped with Global Screening Array-24 v1.0 chip. We selected the 313 SNPs PRS for ER+/HER2- breast cancer from PGS Catalog for evaluation. Quality control, imputation, PRS calculation and statistical analysis were performed in PLINK v2.0, Michigan server, PGS Catalog and R, respectively. We present the preliminary results for 1347 women (504 cases and 843 controls) included until March of 2023. After quality control and imputation, we calculated PRS for 1212 subjects (475 cases and 737 controls). Out of 313 SNPs, 211 were validated in our samples. For ER+/HER2- breast cancer, the odds ratio per SD of the 211-variant PRS (PRS211) was 1.363 (95% confidence interval [CI]: 1.211 to 1.537). Compared with women with average risk (40th-60th PRS percentile), women in the top 10% of PRS211 had a 1.623-fold increased risk (95% CI: 1.047 to 2.522). The area under the receiver operating characteristic curve of 0.581. Our preliminary results indicate that a PRS derived from European-ancestry population correlates with ER+/HER2- breast cancer in admixed Brazilian population, although with attenuated performance. Further work is needed to better characterize PRS risk stratification in admixed populations. Citation Format: Marina Candido Visontai Cormedi, Álison Luís Eburnêo Pereira, Fernanda Borchers Coeli-Lacchini, Sabrina Baroni, Lívia Mara Torres Bueno, Evelyn Ayumi Onga, Victor Girelli Piloto De Oliveira, Fabiana De Oliveira Buono, Aline Fares, Tatiana Strava Correa, Iasmin Alves Chirichela, Fernanda Peria, Romulado Barroso-Sousa, Rodrigo Santa Cruz Guindalini, Taisa Manuela Bonfim Machado Lopes, Rosimeire Aparecida Roela, Maria Aparecida Azevedo Koike Folgueira, Daniel Guimarães Tiezzi, Leandro Machado Colli, Liane Rapatoni. Developing a polygenic risk score for precision prevention of estrogen receptor-positive (ER+)/HER2- breast cancer in Brazilian women [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-03.

Mediating effect of metabolic syndrome in the association of educational attainment with intervertebral disc degeneration and low back pain

The causal association of educational attainment (EA) with intervertebral disc degeneration (IVDD) or low back pain (LBP), and the mediating effect of metabolic syndrome (MetS) in this association, is not studied to date. In this study, using summary statistics of genome-wide association studies primarily conducted in the individuals of European ancestry, Mendelian randomization (MR) analyses were performed to investigate: (1) the total and direct effects of EA on IVDD and LBP, (2) bidirectional associations of EA with MetS or the components of MetS, (3) causal effects of MetS or its components on IVDD and LBP, and (4) mediating effects of MetS or its components on the causal associations of EA with IVDD and LBP. Univariable MR analysis demonstrated that genetically proxied EA was inversely associated with IVDD (ORIVW: 0.90; 95% CI: 0.87–0.92) and LBP (ORIVW: 0.86; 95% CI: 0.84–0.89). Consistent results were obtained after adjusting for potential confounders (cognition, economic level, smoking traits, and metabolic factors). Mediation analysis proved that the effect of EA on IVDD mediated by MetS, waist circumference, and high-density lipoprotein cholesterol was 11.38%, 9.22%, and 2.17%, respectively. Besides, MetS mediated 8.42% and waist circumference mediated 5.81% of the EA effects on LBP, respectively. Our findings provided support for MetS mediating the causal protective effects of EA on IVDD and LBP, which provided causal evidence to the etiology and intervention targets of IVDD and LBP.

Genetic influence on scar vascularity after burn injury in individuals of European ancestry: A prospective cohort study

Genetic influence on scar vascularity after burn injury in individuals of European ancestry: A prospective cohort study

Thyroid Function Impact on Cardiac Structure, Function and Disease Risk: Evidence of Causal Associations in European Ancestry

BackgroundThyroid hormones play a crucial role in cardiovascular physiology. Subclinical thyroid dysfunction has been associated with adverse cardiovascular outcomes, but evidence is mixed regarding causality. ObjectiveTo investigate the potential causal relationships of thyroid-stimulating hormone (TSH), free thyroxine, hypothyroidism, and hyperthyroidism with cardiovascular outcomes, including atrial fibrillation (AF), coronary artery disease, myocardial infarction, heart failure, and ischemic stroke, as well as their impact on cardiac structure and function assessed by cardiac magnetic resonance imaging. MethodsA comprehensive two-sample Mendelian randomization (MR) analysis was conducted, utilizing summary data from large-scale meta-analyses of European ancestry individuals. ResultsGenetically determined lower TSH levels (OR 0.928, 95% CI: 0.884 to 0.974, P = 0.003) and genetic risk of hyperthyroidism (OR 1.049, 95% CI: 1.016 to 1.083, P = 0.003) were associated with increased AF risk. These associations remained significant even after adjusting for cardiovascular risk factors. Colocalization and multivariable MR revealed height as a key mediator between TSH/hyperthyroidism and AF. These findings were further corroborated in the independent FinnGen cohort. However, no clear evidence was found for relationships between thyroid function and other cardiovascular outcomes and cardiac structure and function. ConclusionsOur study shows that reduced TSH levels and hyperthyroidism heighten AF risk, with height serving as an important mediator in these associations. The primary focus of thyroid management in cardiovascular health should be on preventing and treating arrhythmias, particularly AF. Our research highlights the importance of routine screening and timely treatment of thyroid dysfunction to optimize the prevention and management of arrhythmias.

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Understanding the determinants of sweet taste liking in the African and East Asian ancestry groups in the U.S.-A study protocol.

The liking for sweet taste is a powerful driver for consuming added sugars, and therefore, understanding how sweet liking is formed is a critical step in devising strategies to lower added sugars consumption. However, current research on the influence of genetic and environmental factors on sweet liking is mostly based on research conducted with individuals of European ancestry. Whether these results can be generalized to people of other ancestry groups warrants investigation. We will determine the differences in allele frequencies in sweet-related genetic variants and their effects on sweet liking in 426 adults of either African or East Asian ancestry, who have the highest and lowest average added sugars intake, respectively, among ancestry groups in the U.S. We will collect information on participants' sweet-liking phenotype, added sugars intake (sweetness exposure), anthropometric measures, place-of-birth, and for immigrants, duration of time living in the U.S. and age when immigrated. Ancestry-specific polygenic scores of sweet liking will be computed based on the effect sizes of the sweet-related genetic variants on the sweet-liking phenotype for each ancestry group. The predictive validity of the polygenic scores will be tested using individuals of African and East Asian ancestry from the UK Biobank. We will also compare sweet liking between U.S.-born individuals and immigrants within each ancestry group to test whether differences in environmental sweetness exposure during childhood affect sweet liking in adulthood. Expanding genetic research on taste to individuals from ancestry groups traditionally underrepresented in such research is consistent with equity goals in sensory and nutrition science. Findings from this study will help in the development of a more personalized nutrition approach for diverse populations. This protocol has been preregistered with the Center for Open Science (https://doi.org/10.17605/OSF.IO/WPR9E).

Physical activity alters the effect of genetic determinants of adiposity on hypertension among individuals of European ancestry in the UKB.

Hypertension is a leading risk factor for cardiovascular disease and is modulated by genetic variants. This study aimed to assess the effect of obesity genetic liability and physical activity on hypertension among European and African ancestry individuals within the UK Biobank (UKB). Participants were 230 115 individuals of European ancestry and 3239 individuals of African ancestry from UKB. Genetic liability for obesity were estimated using previously published data including genetic variants and effect sizes for body mass index (BMI), waist-hip ratio (WHR) and waist circumference (WC) using Plink software. The outcome was defined as stage 2 hypertension (systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of anti-hypertensive medications). The association between obesity genetic liability and the outcome was assessed across categories of self-reported physical activity using logistic regression. Among European ancestry participants, there was up to a 1.2 greater odds of hypertension in individuals with high genetic liability and low physical activity compared to individuals with low genetic liability and high physical activity (p < 0.001). In individuals engaging in low levels of physical activity compared with moderate/high physical activity, the effect of BMI genetic liability on hypertension was greater (p interaction = 0.04). There was no evidence of an association between obesity genetic liability and hypertension in individuals of African ancestry in the whole sample or within separate physical activity groups (p > 0.05). This study suggests that higher physical activity levels are associated with lower odds of stage 2 hypertension among European ancestry individuals who carry high genetic liability for obesity. This cannot be inferred for individuals of African ancestry, possibly due to the low African ancestry sample size within the UKB.

Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.

Causal relationship between eosinophilic esophagitis and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study.

Eosinophilic esophagitis (EoE) and inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are immune-mediated gastrointestinal diseases with overlapped pathogenesis and are sometimes concurrently diagnosed, but their causal relationship remains unclear. We investigated the causal relationship between EoE and IBD and its subtypes via a two-sample bidirectional Mendelian randomization (MR) approach. MR analyses were performed using summary data of a genome-wide association study (GWAS) on individuals of European ancestry. Independent single-nucleotide polymorphisms correlated with EoE (from a GWAS meta-analysis containing 1,930 cases and 13,634 controls) and IBD (from FinnGen GWASs containing 9,083 IBD, 2,033 CD, and 5,931 UC cases, and GWASs of IBD genetic consortium containing 12,882 IBD, 6,968 UC, and 5,956 CD cases) were selected as instruments. We applied the inverse variance weighted (IVW) method as the primary analysis followed by several sensitivity analyses. For the forward MR study, estimates from IVW methods were subsequently meta-analyzed using a random-effect model. Our results suggested a causal effect of EoE on IBD [pooled odds ratio (OR), 1.07; 95% confidence interval (CI), 1.02-1.13] and EoE on UC (pooled OR, 1.09, 95% CI, 1.04-1.14). No causal link between EoE and CD was observed (pooled OR, 1.05; 95% CI, 0.96-1.16). The reverse MR analyses revealed no causal effect of IBD (and its subtypes) on EoE. Sensitivity analyses confirmed the robustness of primary results. Our findings provided evidence of a suggestive causal effect of EoE on IBD (specifically on UC) in the European population. Increased awareness of concurrent or subsequent IBD in patients with EoE is called for. Still, the present evidence is not adequate enough and ought to be validated by further investigations.

Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score

The extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD. Participants were of European ancestry from the UK Biobank without prevalent CAD. An externally trained genome-wide CAD PRS was generated and then applied. Clinical risk factors were ascertained at baseline. Cox proportional hazards models were fitted to examine the incident CAD effects of CAD PRS, risk factors, and their interactions. Next, the PRS and risk factors were stratified to investigate the attributable risk of clinical risk factors. A total of 357,144 individuals of European ancestry without prevalent CAD were included. During a median of 11.1 years of follow-up (interquartile range 10.4-14.1 years), CAD PRS was associated with 1.35-fold (95% confidence interval [CI] 1.332-1.368) risk per SD for incident CAD. The prognostic relevance of the following risk factors was relatively diminished for those with high CAD PRS on a continuous scale: type 2 diabetes (hazard ratio [HR]interaction 0.91, 95% CIinteraction 0.88-0.94), increased body mass index (HRinteraction 0.97, 95% CIinteraction 0.96-0.98), and increased C-reactive protein (HRinteraction 0.98, 95% CIinteraction 0.96-0.99). However, a high CAD PRS yielded joint risk increases with low-density lipoprotein cholesterol (HRinteraction 1.05, 95% CIinteraction 1.04-1.06) and total cholesterol (HRinteraction 1.05, 95% CIinteraction 1.03-1.06). The CAD PRS is associated with incident CAD, and its application improves the prognostic relevance of several clinical risk factors. P.N. (R01HL127564, R01HL151152, and U01HG011719) is supported by the National Institutes of Health.

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Reverse causation between multiple sclerosis and psoriasis: a genetic correlation and Mendelian randomization study

Observational studies have found a potential bidirectional positive association between multiple sclerosis and psoriasis, but these studies are susceptible to confounding factors. We examined the directionality of causation using Mendelian randomization and estimated the genetic correlation using the linkage disequilibrium score. We performed Mendelian randomization analysis using large-scale genome-wide association studies datasets from the International Multiple Sclerosis Genetics Consortium (IMSGC, 115,803 individuals of European ancestry) and FinnGen (252,323 individuals of European ancestry). We selected several Mendelian randomization methods including causal analysis using summary effect (CAUSE), inverse variance-weighted (IVW), and pleiotropy-robust methods. According to CAUSE and IVW the genetic liability to MS reduces the risk of psoriasis (CAUSE odds ratio [OR] 0.93, p = 0.045; IVW OR 0.93, p = 2.51 × 10–20), and vice versa (CAUSE OR 0.72, p = 0.001; IVW OR 0.71, p = 4.80 × 10–26). Pleiotropy-robust methods show the same results, with all p-values < 0.05. The linkage disequilibrium score showed no genetic correlation between psoriasis and MS (rg = − 0.071, p = 0.2852). In summary, there is genetic evidence that MS reduces the risk of psoriasis, and vice versa.

Clinical features of prostate cancer by polygenic risk score.

Genome-wide association studies have identified more than 290 single nucleotide variants (SNVs) associated with prostate cancer. These SNVs can be combined to generate a Polygenic Risk Score (PRS), which estimates an individual's risk to develop prostate cancer. Identifying individuals at higher risk for prostate cancer using PRS could allow for personalized screening recommendations, improve current screening tools, and potentially result in improved survival rates, but more research is needed before incorporating them into clinical use. Our study aimed to investigate associations between PRS and clinical factors in affected individuals, including age of diagnosis, metastases, histology, International Society of Urological Pathology (ISUP) Grade Group (GG) and family history of prostate cancer, while taking into account germline genetic testing in known prostate cancer related genes. To evaluate the relationship between these clinical factors and PRS, a quantitative retrospective chart review of 250 individuals of European ancestry diagnosed with prostate cancer who received genetic counseling services at The Ohio State University's Genitourinary Cancer Genetics Clinic and a 72-SNV PRS through Ambry Genetics, was performed. We found significant associations between higher PRS and younger age of diagnosis (p = 0.002), lower frequency of metastases (p = 0.006), and having a first-degree relative diagnosed with prostate cancer (p = 0.024). We did not observe significant associations between PRS and ISUP GG, histology or a having a second-degree relative with prostate cancer. These findings provide insights into features associated with higher PRS, but larger multi-ancestral studies using PRS that are informative across populations are needed to understand its clinical utility.

Exploring the relationship between Treg-mediated risk in COPD and lung cancer through Mendelian randomization analysis and scRNA-seq data integration

BackgroundEvidence from observational studies suggests an association between chronic obstructive pulmonary disease (COPD) and lung cancer. The potential interactions between the immune system and the lungs may play a causative role in COPD and lung cancer and offer therapeutic prospects. However, the causal association and the immune-mediated mechanisms between COPD and lung cancer remain to be determined.MethodsWe employed a two-sample Mendelian randomization (MR) approach to investigate the causal association between COPD and lung cancer. Additionally, we examined whether immune cell signals were causally related to lung cancer, as well as whether COPD was causally associated with immune cell signals. Furthermore, through two-step Mendelian randomization, we investigated the mediating effects of immune cell signals in the causal association between COPD and lung cancer. Leveraging publicly available genetic data, our analysis included 468,475 individuals of European ancestry with COPD, 492,803 individuals of European ancestry with lung cancer, and 731 immune cell signatures of European ancestry. Additionally, we conducted single-cell transcriptome sequencing analysis on COPD, lung cancer, and control samples to validate our findings.FindingsWe found a causal association between COPD and lung cancer (odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.31–2.02, P-value < 0.001). We also observed a causal association between COPD and regulatory T cells (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.01–1.40, P-value < 0.05), as well as a causal association between regulatory T cells and lung cancer (odds ratio [OR] = 1.02, 95% confidence interval [CI] = 1.002–1.045, P-value < 0.05). Furthermore, our two-step Mendelian randomization analysis demonstrated that COPD is associated with lung cancer through the mediation of regulatory T cells. These findings were further validated through single-cell sequencing analysis, confirming the mediating role of regulatory T cells in the association between COPD and lung cancer.InterpretationAs far as we are aware, we are the first to combine single-celled immune cell data with two-sample Mendelian randomization. Our analysis indicates a causal association between COPD and lung cancer, with regulatory T cells playing an intermediary role.

Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype–phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10–3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10–131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype–phenotype screens in diverse populations.