Meta-analysis Of Genome-wide Association Studies Research Articles

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.

Genome-wide association study meta-analysis of 9,619 cases with tic disorders

Despite the significant personal and societal burden of tic disorders (TD), treatment outcomes remain modest, necessitating a deeper understanding of their etiology. Family history is the biggest known risk factor and identifying risk genes could accelerate progress in the field. Expanding upon previous sample size limitations, we added 4,800 new TD cases and 971,560 controls, conducting a GWAS meta-analysis with 9,619 cases and 981,048 controls of European ancestry. We attempted to replicate the results in an independent deCODE Genetics GWAS (885 TD cases and 310,367 controls). To characterize GWAS findings, we conducted several post-GWAS gene-based and enrichment analyses. A genome-wide significant hit (rs79244681, p=2.27x10-08) within MCHR2-AS1 was identified, though it was not replicated. Post-GWAS analyses revealed a 13.8% SNP-heritability and three significant genes: BCL11B, NDFIP2, and RBM26. Common variant risk for TD was enriched within genes preferentially expressed in the cortico-striato-thalamo-cortical circuit (including the putamen, caudate, nucleus accumbens, and Brodman area 9) and five brain cell types (excitatory and inhibitory telencephalon-, inhibitory- di- and mesencephalon, hindbrain-, and medium spiny neurons). TD polygenic risk was enriched within loss-of-function intolerant genes (p=0.0017) and high-confidence neurodevelopmental disorder genes (p=0.0108). Of 112 genetic correlations, 43 were statistically significant, showing high positive correlations with most psychiatric disorders. Of the two SNPs previously associated with TD, one (rs2453763) replicated in an independent sub-sample of our GWAS (p=0.00018). This GWAS was still underpowered to identify high-confidence, replicable loci, but the results suggest imminent discovery of common genetic variants for TD.

Genome-wide association studies for pelvic organ prolapse in the Japanese population

Pelvic organ prolapse (POP) affects approximately 40% of elderly women, characterized by the descent of the pelvic organs into the vaginal cavity. Here we present the results of a genome-wide association study (GWAS) for susceptibility to POP comprising 771 cases and 76,625 controls in the Japanese population. We identified a significant association of WT1 locus with POP in the Japanese population; rs10742277; odds ratio (OR) = 1.48, 95% confidence interval (CI), 1.29–1.68, P = 6.72 × 10−9. Subsequent cross-ancestry GWAS meta-analysis combining the Japanese data and previously reported European data, including 28,857 cases and 622,916 controls, identified FGFR2 locus as a novel susceptibility locus to POP (rs7072877; OR = 1.06, 95% CI, 1.04–1.08, P = 4.11 × 10−8). We also observed consistent directions of the effects for 21 out of 24 European GWAS derived loci (binomial test P = 2.8 × 10−4), indicating that most of susceptibility loci for POP are shared across the Japanese and European populations.

Causal effects of pediatric asthma on psychiatric disorders: a bidirectional Mendelian randomization study

Background Previous studies have suggested a potential link between pediatric asthma and psychiatric disorders. However, the causal relationship between pediatric asthma and psychiatric disorders is unclear. Therefore, we used Mendelian randomization to explore causal relationships between pediatric asthma and depression, anxiety disorders, and attention deficit and hyperactivity disorder (ADHD). Methods Genome-wide association studies (GWAS) meta-analyses with the largest possible sample size and independent individuals from European ancestry were selected. The genetic data for depression and anxiety are from FinnGen consortium, while the genetic data for ADHD is from the Psychiatric Genomics Consortium. Inverse variance weighted (IVW) was the main analysis method. The heterogeneity of the instrumental variables (IVs) was assessed using IVW, and the horizontal pleiotropy of the IVs was assessed using MR-Egger. Result The IVW results showed a significant causal relationship between pediatric asthma and depression (OR = 1.08, 95% CI = 1.02–1.15; p = 0.013). However, there is no evidence to suggest a causal relationship between pediatric asthma, anxiety, and ADHD. Reverse MR suggests a significant causal relationship (OR = 1.27, 95% CI [1.14–1.41], p = 9.64E − 06) between ADHD and pediatric asthma using the IVW method. Conclusions Our findings suggest a causal relationship between pediatric asthma and an increased risk of depression. Additionally, we found that ADHD is significantly associated with a higher risk of pediatric asthma.

Causal links between blood inflammation markers and postherpetic neuralgia risk: insights from a two-sample Mendelian randomization study.

Previous studies have suggested an association between blood inflammation-related factors and postherpetic neuralgia. However, the causal relationship between blood inflammation-related factors and postherpetic neuralgia remains unclear. We employed a bidirectional Two-sample Mendelian randomization (MR) analysis to explore the causal relationship between blood inflammation-related factors and postherpetic neuralgia. The instrumental variables were obtained from a large Genome-wide association study (GWAS) meta-analysis dataset of European descent. The instrumental variables of the blood inflammation-related factors come from the database numbers GCST004420 to GCST004460 and GCST90029070. Postherpetic neuralgia has 195,191 samples with a total of 16,380,406 single nucleotide polymorphisms (SNPs). MR analyses were performed using inverse-variance weighted, MR-Egger, and weighted median methods. The MR results revealed a significant causal effect of Macrophage Inflammatory Protein 1 Beta (MIP1β) on reducing the risk of postherpetic neuralgia (95%CI = 0.492-0.991, p = 0.044). Additionally, higher levels of interleukin (IL)-10 (95%CI = 0.973-0.998, p = 0.019) and IL-12p70 (95%CI = 0.973-0.997, p = 0.013) were associated with a lower risk of postherpetic neuralgia. Other inflammatory markers showed no significant causal relationship with this condition. This study identifies MIP1β, IL-10, and IL-12p70 as potential therapeutic targets for preventing or treating postherpetic neuralgia, underscoring the need for further research in this area.

Integrating GWAS and transcriptomics to identify candidate genes conferring relative growth rate trait in white-feathered broiler

Broilers are a globally significant resource for food production, and their relative growth rate (RGR) has attracted increasing attention for improving broiler monitoring, feed management and feed conversion. The main objectives of this study were to identify key candidate genes affecting the RGR in white-feathered broiler by integrating genomic and transcriptomic datasets. This study reports a meta-analysis of genome-wide association studies (GWASs) using three purebred lines (n = 3,727) and 5,841,467 input SNPs to understand the genetic control of the RGR. A total of 101 associated SNPs located on 6 chromosomes were identified, 16 of which were common in the GWASs and meta cohorts. Fine mapping of a significant peak with 7 linked SNPs (r2>0.94) located within the coding region of RAP2C revealed that chr4:3474286 (C>G) among these SNPs was a highly putative causal variant (PIP=19%) and explained 2.26% of the RGR variation. Further analyses indicated that the surface expression level of the RAP2C gene in the blood, macrophage, lung tissue, and cecum tissue of commercial broiler breed (Ross) was higher than in the corresponding tissues of other egg-laying hens and local breeds. In addition, there was a significant difference in the expression of the RAP2C gene between the high (H, n =5) and low (L, n = 4) RGR groups. A total of 301 differentially expressed genes (DEGs) related to the RGR in white-feathered broiler were identified by transcriptome differential analysis between the H and L populations, among which NFKBIA, CSF1R and TLR2A were important hub genes. Furthermore, the candidate genes identified based on GWASs, meta-analysis and DEGs analysis were significantly enriched for gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in the growth cone, integrated-mediated signaling pathway, and MAPK signalling pathway. Overall, the RAP2C, NFKBIA, CSF1R and TLR2A genes are considered the most important candidate genes influencing RGR trait in white-feathered broiler. These findings provide valuable insights into the complex system that regulates broiler growth.

Causal Relationships of Circulating Inflammatory Proteins and Portal Vein Thrombosis: A Mendelian Randomization Study.

Portal vein thrombosis (PVT) is commonly encountered in patients with cirrhosis, challenging our understanding of its development, particularly the ambiguous contribution of inflammation. This study utilized Mendelian randomization (MR) to explore the causal impact of circulating inflammatory markers on PVT.Employing a two-sample MR framework, we merged genome-wide association study (GWAS) meta-analysis findings of 91 inflammation-associated proteins with independent PVT data from the FinnGen consortium's R10 release. A replication analysis was performed using a distinct GWAS dataset from the UK Biobank. Inverse variance weighting, MR-Egger regression, weighted median estimator, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier were used for analysis, supplemented by multivariable MR (MVMR) to adjust for cirrhosis effects.Findings indicate a significant inverse association between the genetically inferred concentration of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and PVT risk, evidenced by an odds ratio (OR) of 0.37 (95% confidence interval [CI]: 0.21-0.67; p = 9.2 × 10-4; adjusted for multiple testing p = 0.084). This association was corroborated in the replication phase (OR = 0.39, 95% CI: 0.17-0.93; p = 0.03) and through MVMR analysis (OR = 0.34, 95% CI: 0.15-0.79; p = 0.012). Sensitivity analyses disclosed no evidence of heterogeneity or pleiotropy.Our investigation emphasizes the 4E-BP1 as a protective factor against PVT, underscoring its potential relevance in understanding PVT pathogenesis and its implications for diagnosis and therapy.

Identification of risk loci for postpartum depression in a genome-wide association study.

Genome-wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD-associated loci. The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders. A meta-analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10-8) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over-represented in categories including long-term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling. The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis.

Dietary eggs, egg nutrients, polygenic score for body mass index, “Western pattern” diet, and weight change, a prospective analysis in the Women's health initiative

Background & AimsEggs contain nutrients which could help enrich the diets of postmenopausal women. Egg consumption and elevated body weight have been associated with elevated risk of serious chronic disease. It is possible that elevated body weight mediates between egg consumption and serious chronic disease. However, few studies exist on the link between egg consumption and body weight in post-menopausal women, and none of them accounted for genetic weight gain predispositions. Our objective was to examine associations between egg consumption, body weight, and genetic predisposition for an elevated Body Mass Index (BMI), in postmenopausal women. MethodsWe analyzed data from 4,439 healthy Women’s Health Initiative participants of European descent during a 6-year follow up using multivariable generalized linear mixed models to prospectively evaluate egg and egg-nutrient intake (measured by a food frequency questionnaire) against body weight and a BMI polygenic score (PGS-BMI) derived from GWAS meta-analysis effect-allele frequencies. ResultsWe found a positive prospective association between change in egg intake and body weight during the 6-year follow up. For instance, at year 3, women whose intake had increased by 2.0 eggs/week had gained 0.70 kg (95%CI: 0.34, 1.07, p=.0002) more than women whose intake had decreased by 2.4 eggs/week, p-linear <.0001. Cholesterol-intake and choline-intake, but not betaine-intake, showed similar significant associations. Exploratory analysis revealed that: 1) women only demonstrated these significant associations if they exhibited higher intakes of “Western-pattern” foods including processed and red meats, French fries, sweets and deserts, sugar-sweetened beverages, fried foods, and dietary fat, and energy; and 2) there was a significant positive prospective association between PGS-BMI and body-weight change, but only in the top quintile of egg-intake change. ConclusionsWe found significant positive prospective associations between weight change and changes in egg intake, cholesterol intake, and choline intake among healthy postmenopausal women of European ancestry in the Women’s Health Initiative. Exploratory analyses revealed that: 1) these significant associations only obtained among women who ate large amounts of “Western-pattern” foods; and 2) women with a higher genetic susceptibility for an elevated BMI gained more weight only if they increased their egg intake considerably. Our results require confirmation.

Genetic Risk, Lifestyle Adherence, and Risk of Developing Hyperuricaemia in a Japanese Population.

To investigate the inter-relationships among genetic risk, healthy lifestyle adherence, and hyperuricaemia susceptibility. This prospective cohort study was conducted with 7,241 hyperuricaemia-free individuals aged ≥ 20 years from the Tohoku Medical Megabank Community-based cohort study. A comprehensive lifestyle score included body mass index, smoking, drinking, and physical activity, and a polygenic risk score (PRS) was constructed based on uric acid loci from a previous genome-wide association study meta-analysis. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and hyperuricaemia incidence and calculate the area under the receiver operating characteristic curve (AUROC). Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dl or a self-reported history of hyperuricaemia. Of the 7,241 adults (80.7% females; mean [SD] age: 57.7 [12.6] years), 217 (3.0%) developed hyperuricaemia during 3.5 years of follow-up. Genetic risk correlated with hyperuricaemia development (P for interaction = 0.287), and lifestyle risks were independently associated. Those with a high genetic risk and poor lifestyle had the highest risk (odds ratio: 5.34; 95% confidence interval [CI]: 2.61-12.10). Although not statistically significant, incorporating the PRS in the model with lifestyle information improved predictive ability (AUROC = 0.771, 95% CI: 0.736-0.806 for lifestyle; AUROC = 0.785, 95% CI: 0.751-0.819 for lifestyle and PRS; p = 0.07). : A healthy lifestyle to prevent hyperuricaemia, irrespective of genetic risk, may mitigate the genetic risk. Genetic risk may complement lifestyle factors in identifying individuals at a heightened hyperuricaemia risk.

Association between iron status, preeclampsia and gestational hypertension: A bidirectional two-sample Mendelian randomization study

BackgroundSeveral recent observational studies have reported that iron overload during pregnancy is associated with preeclampsia (PE) and gestational hypertension (GH). However, the causal association between iron status, PE, and GH is still not clear. MethodsWe performed a two-sample Mendelian randomization (MR) study using the genome-wide association study (GWAS) summary statistics of iron status, included serum iron, ferritin, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) from the largest available GWAS meta-analysis, and the summary statistics of PE and GH were obtained from the FinnGen consortium. Fixed-effect inverse variance weighted (IVW), random-effect IVW, maximum likelihood (ML), MR-Egger regression, weighted median, and MR-PRESSO methods were used. ResultsA total of 21, 58, 28, and 22 SNPs were used as IVs for serum iron, ferritin, TIBC, and TSAT, respectively. The F-statistics of IVs ranged from 95.23 to 421.36. The results of the fixed effects IVW method suggested that for per SD unit increase in serum iron, the risk of PE increases by 24 % (OR = 1.24, 95 % CI: 1.03–1.50, P = 0.02). No significant heterogeneity or horizontal pleiotropy was found. The association between ferritin, TIBC, TSAT and PE were statistically insignificant (P>0.05). Furthermore, the results of each MR methods do not support a causal association between iron status and GH, nor a reverse causal association between PE and GH and iron status. ConclusionThis two-sample MR study provides evidence supporting a causal association between serum iron level and PE.

Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer’s disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.

Connecting genomic and proteomic signatures of amyloid burden in the brain.

Alzheimer's disease (AD) has a high heritable component characteristic of complex diseases, yet many of the genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may be helpful to understand the underlying biology of the disease. We performed a meta-analysis of GWAS of CSF Aβ42 and PET measures combining six independent cohorts (n=2,076). Due to the opposite effect direction of Aβ phenotypes in CSF and PET measures, only genetic signals in the opposite direction were considered for analysis (n=376,599). Polygenic risk scores (PRS) were calculated and evaluated for AD status and amyloid endophenotypes. We then searched the CSF proteome signature of brain amyloidosis using SOMAscan proteomic data (Ace cohort, n=1,008) and connected it with GWAS results of loci modulating amyloidosis. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n=13,409) and PET (n=13,116). This combined approach enabled the identification of overlapping genes and proteins associated with amyloid burden and the assessment of their biological significance using enrichment analyses. After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and nine suggestive hits were annotated. We replicated the APOE loci using the large CSF-PET meta-GWAS and identified multiple AD-associated genes as well as the novel GADL1 locus. Additionally, we found a significant association between the AD PRS and amyloid levels, whereas no significant association was found between any Aβ PRS with AD risk. CSF SOMAscan analysis identified 1,387 FDR-significant proteins associated with CSF Aβ42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was very poor (n=35). The enrichment analysis of overlapping hits strongly suggested several signalling pathways connecting amyloidosis with the anchored component of the plasma membrane, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. The strategy of combining CSF and PET amyloid endophenotypes GWAS with CSF proteome analyses might be effective for identifying signals associated with the AD pathological process and elucidate causative molecular mechanisms behind the amyloid mobilization in AD.

Causal associations between COVID-19 and erectile dysfunction: a Mendelian randomization study.

In this study, we aimed to explore the potential association between COVID-19 infection, hospitalization, severe COVID-19, and erection dysfunction (ED) using the two-sample Mendelian randomization (MR) method. Data pertaining to COVID-19 were extracted from the latest version of the COVID-19 Host Genetics Initiative genome-wide association study (GWAS) meta-analyses (Round 7, April 2022), and outcome data were obtained from the Open GWAS database. We applied various MR analysis methods, including the inverse variance weighted method, weighted median method, and MR-Egger regression. Our investigation revealed a negative causal association between COVID-19 hospitalization and ED (total testosterone levels: beta = -0.026; 95% confidence interval: -0.049 to -0.001). However, no evidence supported causal relationships between COVID-19 infection, hospitalization for COVID-19, or severe COVID-19 and other ED risk factors. The results of this comprehensive MR analysis suggest a negative causal link between COVID-19 hospitalization and total testosterone levels. Nonetheless, COVID-19 (comprising infection, hospitalization, and severe illness) may not directly correlate with an increased risk of ED. These findings imply that COVID-19 may exert a distinct impact on ED through indirect pathways.

Abstract P322: Assessing the causal associations of obstructive sleep apnea syndrome and hypertension: a bidirectional two-sample Mendelian randomization study

Background: Obstructive sleep apnea syndrome (OSA) frequently coexists with hypertension, with 30% to 70% of OSA patients also having hypertension. Conversely, the incidence of OSA in hypertensive patients ranges from 30% to 50%. This study designs a bidirectional Mendelian randomization trial to explore the causal relationship between OSA and hypertension. Methods: The summary data for OSA were sourced from a recent large-scale genome-wide association study (GWAS) meta-analysis, which included 16,761 OSA patients and 201,194 European-ancestry controls from the Finnish biobank. Five SNPs were selected as instrumental variables (IVs) for OSA. The summary data for hypertension were obtained from the UK Biobank GWAS, which included 124,227 hypertension patients and 337,653 European-ancestry controls, making it the largest hypertension dataset in GWAS. From this dataset, 214 SNPs were selected as IVs for hypertension. Multiple MR methods, primarily the inverse variance weighted (IVW) method, were used for analysis. Sensitivity analyses of the MR results were performed using methods such as MR-Egger, and the F-statistic was used to evaluate the IVs. Results: OSA was associated with an increased risk of hypertension (OR=1.053, 95%CI 1.019-1.089, P&lt;0.01), and hypertension was significantly associated with an increased risk of OSA (OR=1.812, 95%CI 1.354-2.425, P&lt;0.001). There was heterogeneity in the bidirectional results (OSA → hypertension, P&lt;0.001; hypertension → OSA, P&lt;0.001), but no horizontal pleiotropy (OSA → hypertension, P=0.666; hypertension → OSA, P=0.556). The selected IVs for OSA and hypertension were strong (OSA-IVs F=14.695; hypertension-IVs F=39.624). Conclusion: This bidirectional MR analysis confirms the causal relationship between OSA and hypertension, with hypertension having a more pronounced effect on the incidence of OSA. OSA patients should regularly monitor their blood pressure and undergo routine physical examinations to detect hypertension early.

Association between cardiovascular risk factors and dilated and hypertrophic cardiomyopathy: Mendelian randomization analysis

Backgroundand aims: Dilated cardiomyopathy is a major cause of heart failure, and hypertrophic cardiomyopathy is a common cause of sudden cardiac death in young adults. Epidemiological studies reporting the association between these cardiomyopathies and common cardiovascular risk factors, including smoking, alcohol, and obesity, are limited, and the published studies are mostly observational, making them vulnerable to bias. Methods and resultsWe performed a two-sample Mendelian randomization analysis to assess whether cardiovascular risk factors were causally associated with dilated and hypertrophic cardiomyopathies. Independent genetic variants associated with body mass index, smoking, and alcohol were selected as instrumental variables, with two sets of instrumental variables utilized for alcohol. Dilated cardiomyopathy data on 355,318 samples and hypertrophic cardiomyopathy data on 489,727 samples were obtained from a European population-based genome-wide association study (GWAS) meta-analysis. The large GWAS data sample size improved the statistical power. Our results showed significant associations between a genetic predisposition for smoking and the risk of dilated cardiomyopathy (odds ratio (OR) = 1.33; 95% confidence level (CI): 1.07–1.67; p = 0.012) and between a genetic predisposition for obesity and the risk of dilated cardiomyopathy (OR = 1.62; 95% CI, 1.30 – 2.02; p = 1.51 × 10-5). The results of the other associations were not significant. ConclusionsThis study suggests that smoking and obesity are causally associated with an increased risk of dilated cardiomyopathy.

Integrating large-scale meta-analysis of genome-wide association studies improve the genomic prediction accuracy for combined pig populations.

The strategy of combining reference populations has been widely recognized as an effective way to enhance the accuracy of genomic prediction (GP). This study investigated the efficiency of genomic prediction using prior information and combined reference population. In total, prior information considering trait-associated single nucleotide polymorphisms (SNPs) obtained from meta-analysis of genome-wide association studies (GWAS meta-analysis) was incorporated into three models to assess the performance of GP using combined reference populations. Two different Yorkshire populations with imputed whole genome sequence (WGS) data (9,741,620 SNPs), named as P1 (1259 individuals) and P2 (1018 individuals), were used to predict genomic estimated breeding values for three live carcass traits, including backfat thickness, loin muscle area, and loin muscle depth. A 10 × 5 fold cross-validation was used to evaluate the prediction accuracy of 203 randomly selected candidate pigs from the P2 population and the reference population consisted of the remaining pigs from P2 and the stepwise added pigs from P1. By integrating SNPs with different p-value thresholds from GWAS meta-analysis downloaded from PigGTEx Project, the prediction accuracy of GBLUP, genomic feature BLUP (GFBLUP) and GBLUP given genetic architecture (BLUP|GA) were compared. Moreover, we explored effects of reference population size and heritability enrichment of genomic features on the prediction accuracy improvement of GFBLUP and BLUP|GA relative to GBLUP. The prediction accuracy of GBLUP using all WGS markers showed average improvement of 4.380% using the P1 + P2 reference population compared with the P2 reference population. Using the combined reference population, GFBLUP and BLUP|GA yielded 6.179% and 5.525% higher accuracies than GBLUP using all SNPs based on the single reference population, respectively. Positive regression coefficients were estimated in relation to the improvement in prediction accuracy (between GFBLUP/BLUP|GA and GBLUP) and the size of the reference as well as the heritability enrichment of genomic features. Compared to the classic GBLUP model, GFBLUP and BLUP|GA models integrating GWAS meta-analysis information increase the prediction accuracy and using combined populations with enlarged reference population size further enhances prediction accuracy of the two approaches. The heritability enrichment of genomic features can be used as an indicator to reflect weather prior information is accurately presented.

Causal associations between insulin and Lp(a) levels in Caucasian population: a Mendelian randomization study

BackgroundNumerous observational studies have demonstrated that circulating lipoprotein(a) [Lp(a)] might be inversely related to the risk of type 2 diabetes (T2D). However, recent Mendelian randomization (MR) studies do not consistently support this association. The results of in vitro research suggest that high insulin concentrations can suppress Lp(a) levels by affecting apolipoprotein(a) [apo(a)] synthesis. This study aimed to identify the relationship between genetically predicted insulin concentrations and Lp(a) levels, which may partly explain the associations between low Lp(a) levels and increased risk of T2D.MethodsIndependent genetic variants strongly associated with fasting insulin levels were identified from meta-analyses of genome-wide association studies in European populations (GWASs) (N = 151,013). Summary level data for Lp(a) in the population of European ancestry were acquired from a GWAS in the UK Biobank (N = 361,194). The inverse-variance weighted (IVW) method approach was applied to perform two-sample summary-level MR. Robust methods for sensitivity analysis were utilized, such as MR‒Egger, the weighted median (WME) method, MR pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out analysis, and MR Steiger.ResultsGenetically predicted fasting insulin levels were negatively associated with Lp(a) levels (β = − 0.15, SE = 0.05, P = 0.003). The sensitivity analysis revealed that WME (β = − 0.26, SE = 0.07, P = 0.0002), but not MR‒Egger (β = − 0.22, SE = 0.13, P = 0.11), supported a causal relationship between genetically predisposed insulin levels and Lp(a).ConclusionOur MR study provides robust evidence supporting the association between genetically predicted increased insulin concentrations and decreased concentrations of Lp(a). These findings suggest that hyperinsulinaemia, which typically accompanies T2D, can partially explain the inverse relationship between low Lp(a) concentrations and an increased risk of T2D.

Depression and the risk of non-alcohol fatty liver disease: Results from a cross-sectional study and a Mendelian randomization analysis

BackgroundPrevious studies have suggested that psychiatric factors may be pathogenic for NAFLD. However, the association between depression and NAFLD is not been consistent, and whether depression plays a causal role in the development of NAFLD remains unclear. MethodsWe extracted data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018 to assess the correlation between depression and NAFLD risk. Based on previous genome-wide association studies (GWAS) meta-analyses on NAFLD and depression, we performed a Mendelian randomization (MR) analysis to explore the causal effect of depression on NAFLD. The primary analysis method used in the MR analysis was inverse variance weighted. ResultsWe ultimately extracted the data from 3878 individuals in the NHANES database to perform the cross-sectional study. Multivariable-adjusted logistic regression showed that depressed individuals had a higher risk of NAFLD than controls (odds ratio [OR] 1.33, 95 % CI 1.03–1.72, p = 0.027) among women. Based on GWAS data, we included 36 genetic variants as instrumental variables to estimate the causal effect of depression on NAFLD risk. The MR analysis revealed a causal association between genetically predicted depression and an increased risk of NAFLD (OR = 1.504, 95 % CI 1.13–2.00, p = 0.005). LimitationsThe consistency of these findings in Eastern populations requires further longitudinal studies. ConclusionsThis cross-sectional study suggested that depression might increase the risk of NAFLD in women. The MR analysis demonstrated that there exists a causal association between genetically predicated depression and NAFLD risk.

No evidence that retinol is protective for skin cancer.

With over 1.5 million new cases annually, skin cancers are the most commonly diagnosed group of cancers worldwide. Among these, melanoma and keratinocyte cancers (KC), comprising squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are predominant. Retinol, a vitamin A derivative, is essential in the regulation of growth and differentiation of epidermal cells. Moreover, retinol exhibits antioxidant properties, protecting the skin against ultra-violet (UV) radiation induced oxidative damage. Existing research on the impact of retinol on melanoma, SCC and BCC development shows mixed results. Several dietary intake studies have suggested that higher retinol levels reduce skin cancer risk, however, others have failed to find this association. We used two-sample Mendelian randomization (MR) to explore if there is a causal relationship between retinol and the risk of developing melanoma, SCC or BCC. Genetically predicted circulating retinol levels were obtained from a genome wide association study (GWAS) meta-analysis of the INTERVAL (N=11,132) and METSIM (N=6,136) cohorts. Melanoma (30,134 cases and 375,188 controls), SCC (10,557 cases and 537,850 controls) and BCC (36,479 cases and 540,185 controls) risks were derived from published GWAS meta-analyses. We conducted two MR approaches. In the first MR we used a single SNP (rs10882283) that is associated with the levels of Retinol Binding Protein 4 (RBP4) as an instrument variable (IV) for circulating retinol levels. In the second MR we used all independent genetic variants that were strongly associated (P < 5 × 10-8) with retinol levels as IVs. Odds ratios (OR) for skin cancer were calculated for a one standard deviation (SD) increase in genetically predicted retinol levels. The single IV approach revealed that retinol levels were not significantly associated with risk of melanoma (OR = 1.04 [95% confidence interval 0.83, 1.31], P = 0.72), SCC (OR = 1.15 [0.87, 1.51], P = 0.32) or BCC (OR = 1.06 [0.90, 1.23], P = 0.50). Similar null results were observed with the multiple IV approach for melanoma (OR = 1.03 [0.95, 1.11], P = 0.54), SCC (OR = 1.01 [0.91, 1.13], P = 0.83), and BCC (OR = 1.04 [0.96, 1.12], P = 0.38). In conclusion, we found no evidence that circulating retinol levels were causally associated with the development of melanoma, SCC and BCC.