Previous Genome-wide Association Studies Research Articles

Genome-Wide Association Study of Temporomandibular Disorder-Related Pain in Finnish Populations.

Temporomandibular disorders (TMD) are multifactorial musculoskeletal pain and dysfunctions in temporomandibular joints (TMJs) and masticatory muscles. Genetic factors play a role in TMD-related pain, but only a few genome-wide association studies (GWAS) have been conducted. The aim of this GWAS was to explore genetic factors associated with painful TMD in Finnish populations. Data from two epidemiological surveys, the Northern Finland Birth Cohort 1966 (NFBC1966) and the Health 2000 Survey in Finland, including altogether 468 cases and 6833 controls, were used. Case definition was based on pain on palpation of masticatory muscles and/or TMJs. GWASs of the whole data and stratified by sex were conducted from both cohorts using additive models, followed by meta-analysis of the two cohorts. Replications of the previously reported TMD risk loci (rs73460075, DMD; rs4794106, SGCA; rs73271865, SP4; rs60249166, RXP2; rs1531554, BAHCCI; rs5862730, OTUD4/SMAD1; rs10092633, SFRP1; rs34612513, SOX14/CLDN18; rs878962, TSPAN9) were also investigated. Four genome-wide significant loci were found in sex-stratified analysis of NFBC1966, including associations at three loci in males (rs1023114, PRIM2, p = 5 × 10-9; rs4244867, ALG10, p = 3 × 10-8; rs79841648, ADCYAP1, p = 4 × 10-9) and one locus in females (rs148476652, DNER, p = 4 × 10-9). However, the results could not be replicated in the Health 2000 Survey or in the meta-analysis of these two cohorts. The previous TMD GWAS associations did not replicate in our data either. Several TMD pain-associated variants were found in sex-stratified analysis of NFBC1966, suggesting the role of neuroendocrine stress responses and central nervous system. These findings need to be confirmed in future studies.

Whole exome sequencing identified six novel genes for depressive symptoms.

Previous genome-wide association studies of depression have primarily focused on common variants, limiting our comprehensive understanding of the genetic architecture. In contrast, whole-exome sequencing can capture rare coding variants, helping to explore the phenotypic consequences of altering protein-coding genes. Here, we conducted a large-scale exome-wide association study on 296,199 participants from the UK Biobank, assessing their depressive symptom scores through the Patient Health Questionnaire-4. We identified 22 genes associated with depressive symptoms, including 6 newly discovered genes (TRIM27, UBD, SVOP, ADGRB2, IRF2BPL, and ANKRD12). Both ontology enrichment analysis and plasma proteomics association analysis consistently revealed that the identified genes were associated with immune responses. Furthermore, we identified associations between these genes and brain regions related to depression, such as anterior cingulate cortex and orbitofrontal cortex. Additionally, phenome-wide association analysis demonstrated that TRIM27 and UBD were associated with neuropsychiatric, cognitive, biochemistry, and inflammatory traits. Our findings offer new insights into the potential mechanisms and genetic architecture of depressive symptoms.

Does PhenoAge acceleration impact adverse outcomes following major surgery (rehospitalization or death)? A genome-wide association study and mendelian randomisation

Abstract Background Biological aging reflects the state of an individual's cellular and molecular function, and is distinct from chronological age; which reflects the passage of time[1]. Validated measures of biological aging, such as Phenotypic aging (PhenoAge) estimated from nine routine clinical biomarkers, have been associated with increased risk of age-related diseases and mortality in cohort studies[2]. However, the potential causal relationship between them remains unclear. In this study, we aim to identify genetic variants associated with PhenoAge Acceleration (PhenoAgeAccl) and adverse outcome after surgery (rehospitalisation or death within 365-days] and assess the causal relationship between these two phenotypes using Mendelian Randomization framework. Objectives -Perform a genome-wide association study(GWAS) on adverse outcomes following major surgery. -Assess the potential causal relationship between PhenoAgeAccl and adverse outcomes following major surgery using Mendelian randomization analysis. Methods We conducted a GWAS via plink using participants from the UKBiobank (Application 77596) to generate summary statistics for 6509 participants who had undergone major surgery within 365 days of their baseline assessment date(3). For quality control, SNPs were excluded if they didn't meet the following criteria: (1) imputation information score <0.3 (2) minor allele frequency <1%, (3) Hardy–Weinberg equilibrium test p-value significant at the Bonferroni-corrected level. Summary statistics for PhenoAgeAccl was obtained from a previous GWAS of European descents[4]. Gene enrichment analysis was performed using Multi-marker Analysis of GenoMic Annotation (MAGMA) in Functional Mapping and Annotation (FUMA). Then, genetic instruments for PhenoAgeAccl and adverse outcomes following surgery were identified to conduct a summary-based Mendelian Randomisation [Assumptions are listed in Figure 1]. Results GWAS for adverse outcomes following major surgery identified 3 lead SNPs (rs1360618, rs11848297, rs7978) [Figure 2]. Gene-set analysis showed enrichment in the immune system, cell migration, fear response, and iron metabolism. For PhenoAge Acceleration, gene-set analysis showed enrichment in immune system, and cell signalling pathways. 17 SNPs were selected which were used for the Two-Sample MR. We found no causal relationship, as the beta coefficient for Inverse variance weighted was -0.308 [standard error - 0.075, p=0.68]. For every 5-year increase in PhenoAge compared to chronological age, the risk of emergency re-hospitalisation or death increased by 21% (HR 1.16 – 1.3, p < 0.001). Conclusion Gene-set analysis for adverse outcomes following major surgery showed enrichment in immune system, iron metabolism, and fear response which have all recently been associated with mortality post-surgery in cohort studies(4,5). No causal relationship between PhenoAgeAccel and mortality post-surgery was established.Mendelian Randomisation assumptionsManhattan plot adverse-outcomes post-sur

Association of polymorphisms in the HTRA1 gene with myopia

PurposeTo evaluate the associations of single-nucleotide polymorphisms (SNPs) in the high-temperature requirement protease A 1 (HTRA1) gene with myopia.Methods25 SNPs in HTRA1 were selected, including 23 haplotype-tagging SNPs, SNP rs2142308...

Genome of Russian Snow-White Chicken Reveals Genetic Features Associated with Adaptations to Cold and Diseases.

Russian Snow White (RSW) chickens are characterized by high egg production, extreme resistance to low temperatures, disease resistance, and by the snow-white color of the day-old chicks. Studying the genome of this unique chicken breed will reveal its evolutionary history and help to understand the molecular genetic mechanisms underlying the unique characteristics of this breed, which will open new breeding opportunities and support future studies. We have sequenced and made a de novo assembly of the whole RSW genome using deep sequencing (250×) by the short reads. The genome consists of 40 chromosomes with a total length of 1.1 billion nucleotide pairs. Phylogenetic analysis placed the RSW near the White Leghorn, Fayoumi, and Houdan breeds. Comparison with other chicken breeds revealed a wide pool of mutations unique to the RSW. The functional annotation of these mutations showed the adaptation of genes associated with the development of the nervous system, thermoreceptors, purine receptors, and the TGF-beta pathway, probably caused by selection for low temperatures. We also found adaptation of the immune system genes, likely driven by selection for resistance to viral diseases. Integration with previous genome-wide association studies (GWAS) suggested several causal single nucleotide polymorphisms (SNPs). Specifically, we identified an RSW-specific missense mutation in the RALYL gene, presumably causing the snow-white color of the day-old chicks, and an RSW-specific missense mutation in the TLL1 gene, presumably affecting the egg weight.

Association of plasma arachidonic acid levels with a bipolar disorder and the effects of a FADS gene variant

Recent genome-wide association studies (GWASs) have identified fatty acid desaturase (FADS) genes, which code key enzymes involved in polyunsaturated fatty acid (PUFA) desaturation as susceptibility genes for bipolar disorder (BD). Several quantitative changes in PUFAs suggest their involvement in BD pathogenesis. Therefore, this study aimed to clarify the relationship between BD and PUFAs by conducting lipidomics covariating with the FADS gene variant (rs174550), which is associated with PUFA levels and BD susceptibility. The concentrations of 23 fatty acids were measured using plasma samples from the BD group (n = 535) and the control group (n = 107). Differences in each PUFA concentration ratio were compared between the two groups. Also, differences in each PUFA concentration ratio were compared for each genotype in rs174550. Our results showed that the BD group had significantly lower concentrations of linoleic acid (LA) (β = −0.36, p = 0.023) and arachidonic acid (AA) (β = −0.18, p = 0.013) than the control group. Concerning the effect of FADS on the PUFA concentration ratio, carriers of C-allele at rs174550 had significantly decreased γ-linolenic acid and AA concentration ratios. A previous GWAS reported that the presence of a C-allele at rs174550 increased the BD risk. This direction is consistent with the lipidomic results of the present study. In conclusion, both the FADS and BD were considered to regulate the AA concentration. Thus, as the FADS gene variant is crucial for conducting lipidomics of BD we believe that the allele frequency of FADS must be analyzed.

A genetically informed study reveals modifiable pathways in skin cancer

BackgroundIdentifying modifiable risk factors is essential for the prevention of skin cancer; however, establishing causality can be challenging in conventional epidemiological studies. This study aimed to determine the causal associations of potentially modifiable risk factors with skin cancer using Mendelian randomization (MR).MethodsGenetic instruments for 53 risk factors, including socioeconomic status, dietary and lifestyle factors, anthropometric measures, medication use, and comorbidities, were identified from previous genome-wide association studies. Two-sample MR analyses were performed using summary statistics for three major types of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Findings were verified using multiple MR methods under different assumptions and replication datasets.ResultsGenetic liability to sunburn occasions, actinic keratosis, and prior skin cancers was associated with a higher risk of all three types of skin cancer, whereas genetic liability to vitiligo was associated with a lower risk. For specific skin cancer types, genetically predicted higher nevus counts and occupational class were associated with an increased risk of melanoma. Genetic liability to rheumatoid arthritis, type 2 diabetes, and increased physical activity were associated with a lower risk of BCC. Genetically predicated body mass index showed a negative association with BCC, and a positive association with SCC.ConclusionsOur study reaffirmed several previously established risk factors and identified novel potential risk factors for skin cancer. Further work is needed to unravel the biological pathways in different skin cancer types and translate our findings to inform public health policies.

Translation of genome-wide association study: from genomic signals to biological insights.

Since the turn of the 21st century, genome-wide association study (GWAS) have successfully identified genetic signals associated with a myriad of common complex traits and diseases. As we transition from establishing robust genetic associations with diverse phenotypes, the central challenge is now focused on characterizing the underlying functional mechanisms driving these signals. Previous GWAS efforts have revealed multiple variants, each conferring relatively subtle susceptibility, collectively contributing to the pathogenesis of various common diseases. Such variants can further exhibit associations with multiple other traits and differ across ancestries, plus disentangling causal variants from non-causal due to linkage disequilibrium complexities can lead to challenges in drawing direct biological conclusions. Combined with cellular context considerations, such challenges can reduce the capacity to definitively elucidate the biological significance of GWAS signals, limiting the potential to define mechanistic insights. This review will detail current and anticipated approaches for functional interpretation of GWAS signals, both in terms of characterizing the underlying causal variants and the corresponding effector genes.

Genetic variants of LRRC8C, OAS2, and CCL25 in the T cell exhaustion-related genes are associated with non-small cell lung cancer survival.

T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported. We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants. Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood. Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression.

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 and genomic prediction for growth traits in spotted sea bass (Lateolabrax maculatus) using insertion and deletion markers

AbstractSpotted sea bass (Lateolabrax maculatus) is a species of significant economic importance in aquaculture. However, genetic degeneration, such as declining growth performance, has severely impeded industry development, necessitating urgent genetic improvement. Here, we conducted a genome‐wide association study (GWAS) and genomic prediction for growth traits using insertion and deletion (InDel) markers, and systematically compared the results with our previous studies using single nucleotide polymorphism (SNP) markers. A total of 97 significant InDels including a 6 bp insertion in an exon region were identified. It is worth noting that only 5 and 1 candidate genes for DY and TS populations were also detected in previous GWAS using SNPs, and numerous novel genes including c4b, fgf4, and dnajb9 were identified as vital candidate genes. Moreover, several novel growth‐related procedures, such as the growth and development of the bone and muscle, were also detected. These findings indicated that InDel‐based GWAS can provide valuable complement to SNP‐based studies. The comparison of genomic predictive performance for total length trait under different marker selection strategies and genomic selection models indicated that GWAS selection strategy exhibits more stable predictive performance compared to the evenly selection strategy. Additionally, support vector machine model demonstrated better predictive accuracy and efficiency than traditional best linear unbiased prediction and Bayes models. Furthermore, the superior predictive performance using InDel markers compared to SNP markers highlighted the potential of InDels to enhance genomic predictive accuracy and efficiency. Our results carry significant implications for dissecting genetic mechanisms and contributing genetic improvement of growth traits in spotted sea bass through genomic resources.

Associations of genetic variants for refractive error and axial length in adults with ocular endophenotypes in children: a cross-sectional and longitudinal study

AimsTo investigate the associations of genetic variants previously linked to axial length (AL) and spherical equivalent refraction (SE) in adults with refractive error and related endophenotypes in children, at baseline...

Multi-step gene set analysis identified HTR3 family genes involving childhood acute lymphoblastic leukemia susceptibility.

In our previous conventional genome-wide association study (GWAS), WWOX was a susceptibility gene associated with acute lymphoblastic leukemia (ALL) development. Nowadays, advancements in genetic association analyses promote an in-depth exploration of ALL genomics. We conducted a two-step enrichment analysis at both gene and pathway levels based on ALL GWAS data including 269 cases and 1039 controls of Chinese descent. The following functional prediction and experiments were used to evaluate the genetic biology of candidate variants and genes. The serotonin-activated cation-selective channel complex gene-set was a potential biological pathway involved in ALL occurrence. Of which, individuals carrying the T allele of rs33940208 exhibited a prominent reduced risk of ALL [odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.53 to 0.96, P = 2.81 × 10-2], whereas those with the A allele of rs6779545 demonstrated an increased risk (OR = 1.23, 95% CI = 1.01 to 1.51, P = 4.11 × 10-2). Notably, the two variants displayed a better prediction capability when combined, that the risk of developing childhood ALL increased by 131% in subjects with 2-4 risk alleles compared to those with 0-1 risk alleles (Ptrend = 2.05 × 10-3). In addition, the T allele of rs33940208 could reduce HTR3A mRNA level, while the A allele of rs6779545 increased HTR3D mRNA expression. In this study, we identified HTR3A rs33940208 and HTR3D rs6779545 as potential susceptibility loci for ALL in Chinese children. Future validation and functional research will elucidate the underlying molecular processes, refining preventive strategies for this disease.

The causal relationship between cholecystectomy and IBD/IBS and the role of bile acids and gut microbiota: a two-sample Mendelian randomization study

ObjectiveThis study aims to explore the causal relationship between cholecystectomy and inflammatory bowel disease (IBD)/irritable bowel syndrome (IBS) and the role of serum bile acids and gut microbiota in this context.MethodsUtilizing genetic variant data from previous Genome-Wide Association Studies (GWAS), this study employed a two-sample MR approach to assess the causal effect of cholecystectomy on IBD/IBS.ResultsThe MR analysis suggested a potential negative causal relationship between cholecystectomy and UC (p = 0.0233, OR 0.9773, 95%CI 0.9581–0.9969) and a positive causal relationship between cholecystectomy and IBS (p = 0.0395, OR 4.077, 95%CI 1.0699–15.5362). Various sensitivity analyses reinforced the reliability of the causal relationship. However, the analysis did not find definitive results between serum bile acids or gut microbiota and cholecystectomy or IBD/IBS, possibly due to insufficient statistical power. MVMR find a causal relationship between bile acids and IBS (p = 0.0015, b = 0.4085) and UC (p = 0.0198, b = 0.0029).ConclusionThis study provides evidence of a causal relationship between cholecystectomy and IBD/IBS, highlighting the potential risk reduction for UC and increased risk for IBS following cholecystectomy. The role of bile acids and gut microbiota in this relationship remains unclear, necessitating further research to validate the causality and explore underlying mechanisms.

Identification of Quantitative Trait Loci Associated with Plant Adaptation Traits Using Nested Association Mapping Population.

This study evaluated 290 recombinant inbred lines (RILs) of the nested association mapping (NAM) population from the UK. The population derived from 24 families, where a common parent was "Paragon," one of the UK's spring wheat cultivar standards. All genotypes were tested in two regions of Kazakhstan at the Kazakh Research Institute of Agriculture and Plant Industry (KRIAPI, Almaty region, Southeast Kazakhstan, 2019-2022 years) and Alexandr Barayev Scientific-Production Center for Grain Farming (SPCGF, Shortandy, Akmola region, Northern Kazakhstan, 2019-2022 years). The studied traits consisted of plant adaptation-related traits, including heading date (HD, days), seed maturation date (SMD, days), plant height (PH, cm), and peduncle length (PL, cm). In addition, the yield per m2 was analyzed in both regions. Based on a field evaluation of the population in northern and southeastern Kazakhstan and using 10,448 polymorphic SNP (single-nucleotide polymorphism) markers, the genome-wide association study (GWAS) allowed for detecting 74 QTLs in four studied agronomic traits (HD, SMD, PH, and PL). The literature survey suggested that 16 of the 74 QTLs identified in our study had also been detected in previous QTL mapping studies and GWASs for all studied traits. The results will be used for further studies related to the adaptation and productivity of wheat in breeding projects for higher grain productivity.

GWAS and polygenic risk score of severe COVID-19 in Eastern Europe.

COVID-19 disease has infected more than 772 million people, leading to 7 million deaths. Although the severe course of COVID-19 can be prevented using appropriate treatments, effective interventions require a thorough research of the genetic factors involved in its pathogenesis. We conducted a genome-wide association study (GWAS) on 7,124 individuals (comprising 6,400 controls who had mild to moderate COVID-19 and 724 cases with severe COVID-19). The inclusion criteria were acute respiratory distress syndrome (ARDS), acute respiratory failure (ARF) requiring respiratory support, or CT scans indicative of severe COVID-19 infection without any competing diseases. We also developed a polygenic risk score (PRS) model to identify individuals at high risk. We identified two genome-wide significant loci (P-value <5 × 10-8) and one locus with approximately genome-wide significance (P-value = 5.92 × 10-8-6.15 × 10-8). The most genome-wide significant variants were located in the leucine zipper transcription factor like 1 (LZTFL1) gene, which has been highlighted in several previous GWAS studies. Our PRS model results indicated that individuals in the top 10% group of the PRS had twice the risk of severe course of the disease compared to those at median risk [odds ratio = 2.18 (1.66, 2.86), P-value = 8.9 × 10-9]. We conducted one of the largest studies to date on the genetics of severe COVID-19 in an Eastern European cohort. Our results are consistent with previous research and will guide further epidemiologic studies on host genetics, as well as for the development of targeted treatments.

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.

Causal link between childhood obesity and adult osteoporosis: An investigation through Mendelian randomization.

The intricate link between childhood obesity and adult osteoporosis has been a subject of numerous clinical inquiries, yet the genetic underpinnings of this association remain enigmatic. Our research aims to unravel the association between adult osteoporosis and childhood obesity using genome-wide association study data for Mendelian randomization (MR) analysis. Utilizing a pool of single-nucleotide polymorphism data associated with childhood obesity obtained from a previous genome-wide association study report involving a study population of 13,848 people in Europe, alongside data of adult osteoporosis sourced from Neale Lab (5266 cases and 331,893 controls). Various methods for MR were used in our research, including weighted mode, simple mode, weighted median, MR-Egger, and the inverse-variance weighted (IVW). We also used Cochran Q test of IVW to assess for heterogeneity, MR-Egger intercept and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis for pleiotropy, and leave-one-out analysis for the result stability. The instrumental variables associated with 11 single-nucleotide polymorphisms were selected. MR analyses unveiled a noteworthy link between genetically forecasted childhood obesity and the onset of adult osteoporosis based on the odds ratio, 95% confidence interval, and P-value from the results of IVW, MR-Egger, weighted median: simple mode, and weighted mode analyses. No significant heterogeneity was found by the assessment using MR-Egger and IVW. Similarly, there was no indication of pleiotropy based on the MR-PRESSO and MR-Egger analyses. Leave-one-out analysis confirmed the stability of the results. Our research suggests that childhood obesity, as predicted by genetic factors, may pose a significant risk for the development of osteoporosis in adulthood.

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.

Genetic factors and symptom dimensions associated with antidepressant treatment outcomes: clues for new potential therapeutic targets?

Treatment response and resistance in major depressive disorder (MDD) show a significant genetic component, but previous studies had limited power also due to MDD heterogeneity. This literature review focuses on the genetic factors associated with treatment outcomes in MDD, exploring their overlap with those associated with clinically relevant symptom dimensions. We searched PubMed for: (1) genome-wide association studies (GWASs) or whole exome sequencing studies (WESs) that investigated efficacy outcomes in MDD; (2) studies examining the association between MDD treatment outcomes and specific depressive symptom dimensions; and (3) GWASs of the identified symptom dimensions. We identified 13 GWASs and one WES of treatment outcomes in MDD, reporting several significant loci, genes, and gene sets involved in gene expression, immune system regulation, synaptic transmission and plasticity, neurogenesis and differentiation. Nine symptom dimensions were associated with poor treatment outcomes and studied by previous GWASs (anxiety, neuroticism, anhedonia, cognitive functioning, melancholia, suicide attempt, psychosis, sleep, sociability). Four genes were associated with both treatment outcomes and these symptom dimensions: CGREF1 (anxiety); MCHR1 (neuroticism); FTO and NRXN3 (sleep). Other overlapping signals were found when considering genes suggestively associated with treatment outcomes. Genetic studies of treatment outcomes showed convergence at the level of biological processes, despite no replication at gene or variant level. The genetic signals overlapping with symptom dimensions of interest may point to shared biological mechanisms and potential targets for new treatments tailored to the individual patient's clinical profile.