Large Genome-wide Association Studies Research Articles

Evaluating the causal association between bronchiectasis and different types of inflammatory bowel disease: a two-sample Mendelian randomization study.

Previous observational studies have established a connection between bronchiectasis and inflammatory bowel disease (IBD), but none of these studies have provided a clear explanation for the underlying cause of this relationship. The present study thus implemented Mendelian randomization (MR) design to explore possible bidirectional relationships between IBD and bronchiectasis risk, with an additional focus on Crohn's disease (CD) and ulcerative colitis (UC) as IBD subtypes. A large genome-wide association study (GWAS)-derived data pool was leveraged to examine the relationships between bronchiectasis and IBD, CD, and UC. Two-sample MR analyses were performed with an inverse variance weighted (IVW) approach supplemented with the MR-Egger and weighted median methods. Sensitivity analyses were used to further assess the reliability of the main MR study findings. The possibility of reverse causation was also evaluated using a reverse MR approach. The IVW MR analytical approach revealed that IBD (p = 0.074), UC (p = 0.094), and CD (p = 0.644) had no significant impact on the incidence of bronchiectasis, with the converse also being true (p = 0.471, p = 0.700, and p = 0.099, respectively). This MR analysis demonstrated that the higher occurrence of bronchiectasis in patients with IBD is not caused by genetic predisposition.

Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease.

Late-onset Alzheimer's disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

The causal relationship between atopic dermatitis and brain cancer: A bidirectional Mendelian randomization study.

Atopic dermatitis ranks among the prevalent skin disorders. Research has indicated a potential association with brain cancer. Yet, establishing a direct causal relationship between atopic dermatitis and brain cancer continues to be challenging. We extracted single nucleotide polymorphisms (SNPs) significantly associated with atopic dermatitis (sample size=382 254) at a genome-wide level from a large Finnish Genome-Wide Association Study (GWAS) dataset (n cases=15 208, n controls=367 046). Summary data for 372 622 cases of brain cancer (n cases=606, n controls=372 016) were obtained via the IEU Open GWAS database. We employed the Inverse Variance Weighted (IVW) method as our primary analytical approach for Mendelian Randomization (MR) analysis. Additionally, heterogeneity was measured using Cochran's Q value, and horizontal pleiotropy was evaluated using MR-Egger 、Mendelian Randomization Pleiotropy RESidual Sum and Outlier and leave-one-out analyses. The risk of brain cancer increases with the presence of atopic dermatitis, as evidenced by the odds ratios (ORs) and 95% confidence intervals (CIs),(OR=1.0005; 95% CI=1.0001, 1.0009;p=0.0096). However, when conducting the analysis in reverse, no significant link was observed. The findings from our study indicate a causative link between atopic dermatitis and brain cancer, highlighting the importance of conducting broader clinical investigations into their potential association going forward.

Major depressive disorder increased the risk of hypertension: A Mendelian randomization study

BackgroundDespite the high prevalence of comorbid hypertension in patients with major depressive disorder (MDD), the relationship between the two diseases has received little attention. Previous observational studies have descripted the association between MDD and hypertension, the causality from MDD on hypertension remained unknown. The present Mendelian randomization (MR) study aimed to assess the causal effect of MDD on hypertension. MethodsA set of genetics instrument was used for analysis, derived from publicly available genetic meta-analysis data. A total of 44 single-nucleotide polymorphisms (SNPs) associated with MDD. The largest genome-wide association study (GWAS) for hypertension (54,358 cases and 408,652 controls) was used to assess the effect of MDD on hypertension. Inverse variance weighted method (IVW), weighted median method (WM), and MR-Egger regression were used for MR analyses. The MR-Egger_intercept test and Cochran's Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. ResultsA total of 28 independent and effective MDD genetic instrumental variables were extracted from the hypertension GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 28 selected MDD genetic instrument variants in hypertension GWAS datasets. As MDD based on genetic changes increased, the risk of hypertension increased using MR-Egger (OR = 1.004436, 95%CI 0.9884666–1.020663, P = 0.5932928), WM (OR = 1.000499, 95%CI 1.0000188–1.000980, P = 0.0416871), and IVW (OR = 1.000573, 95%CI 1.0000732–1.001074, P = 0.0246392). Our results were robust, with no obvious bias based on investigating the single MDD SNP on hypertension. ConclusionsOur result suggested a causal associated between genetically increased MDD and increased hypertension risk in European population.

Mendelian randomization analysis using GWAS and eQTL data to investigate the relationship between chronotype and neuropsychiatric disorders and their molecular basis.

Chronotype is a proxy sleep measure that has been associated with neuropsychiatric disorders. By investigating how chronotype influences risk for neuropsychiatric disorders and vice versa, we may identify modifiable risk factors for each phenotype. Here we used Mendelian randomization (MR), to explore causal effects by (1) studying the causal relationships between neuropsychiatric disorders and chronotype and (2) characterizing the genetic components of these phenotypes. Firstly, we investigated if a causal role exists between five neuropsychiatric disorders and chronotype using the largest genome-wide association studies (GWAS) available. Secondly, we integrated data from expression quantitative trait loci (eQTLs) to investigate the role of gene expression alterations on these phenotypes. Evening chronotype was causal for increased risk of schizophrenia and autism spectrum disorder and schizophrenia was causal for a tendency toward evening chronotype. We identified 12 eQTLs where gene expression changes in brain or blood were causal for one of the phenotypes, including two eQTLs for SNX19 in hippocampus and hypothalamus that were causal for schizophrenia. These findings provide important evidence for the complex, bidirectional relationship that exists between a sleep-based phenotype and neuropsychiatric disorders, and use gene expression data to identify causal roles for genes at associated loci.

Genetic insight into putative causes of xanthelasma palpebrarum: a Mendelian randomization study.

Xanthelasma palpebrarum (XP) is the most common form of cutaneous xanthoma, with a prevalence of 1.1%~4.4% in the population. However, the cause of XP remains largely unknown. In the present study, we used Mendelian randomization to assess the genetic association between plasma lipids, metabolic traits, and circulating protein with XP, leveraging summary statistics from large genome-wide association studies (GWAS). Genetically predicted plasma cholesterol and LDL-C, but not HDL-C or triglyceride, were significantly associated with XP. Metabolic traits, including BMI, fasting glucose, type 2 diabetes, systolic and diastolic blood pressure, were not significantly associated with XP. Furthermore, we found genetically predicted 12 circulating proteins were associated with XP, including FN1, NTM, FCN2, GOLM1, ICAM5, PDE5A, C5, CLEC11A, CXCL1, CCL2, CCL11, CCL13. In conclusion, this study identified plasma cholesterol, LDL-C, and 12 circulating proteins to be putative causal factors for XP, highlighting the role of plasma cholesterol and inflammatory response in XP development.

No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies.

The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females with ADHD (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk was found, neither in males (inverse-variance weighted (IVW): beta = 0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta = 0.24, 95%-CI [0.09, 0.39]). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.

Abstract 6614: Integrating single-cell RNA-seq and large genome-wide association study data to identify colorectal cancer cell-of-origin populations

Abstract Background: Single-cell RNA sequencing (scRNA-seq) enables the precise identification of distinct cell populations and the measurement of gene expression within each population. Recently, integrating scRNA-seq and genome-wide association study (GWAS) data has shown promise in identifying cell-of-origin populations in human diseases. Colorectal cancer (CRC) progresses through a phenotypic continuum from normal colon to adenoma, and ultimately CRC. However, the specific disease cell-of-origin populations underlying each stage of CRC development at a single-cell resolution have not been well studied. Additionally, while transcriptome-wide association studies (TWAS) have identified more than 200 putative risk genes in CRC, the precise disease cell-of-origin populations associated with these genes remain elusive. Materials and methods: We analyzed scRNA-seq datasets from 31 normal colon, 8 colon serrated polyps, and 15 conventional adenoma tissues of individuals participated the Colorectal Molecular Atlas Project (COLON MAP). We next conducted an integrative analysis of the aforementioned scRNA-seq data, with extensive epigenomics data and summary statistics from a large CRC GWAS conducted among European ancestry populations (78,473 CRC cases and 107,143 controls) using single-cell disease relevance score (scDRS), to investigate cell-of-origin populations underlying the CRC development. We conducted correlation analysis between gene expression and individual cell risk scores derived from scDRS. Additionally, we performed differential expression analysis comparing disease cell-of-origin populations with other cell populations at each stage. Results: We identified multiple cell-of-origin populations associated with CRC, including absorptive cells (ABS) (P < 1 × 10-4) and goblet cells (GOB) (P < 7 × 10-3) in the normal colon, ABS (P < 2 × 10-3), enteroendocrine cells (EE) (P < 0.04), and serrated-specific cells (SSC) (P < 1 × 10-4) in serrated polyps, and ABS (P < 9 × 10-3) and SSC (P < 6 × 10-4) in adenomas. Among the previously reported 205 risk genes from TWAS, a majority show high correlations of their expressions with the risk scores of the single cells (median value R2 = 0.07, 0.14, 0.137 at normal colon, serrated polyps, adenoma, respectively). Moreover, 57 of these TWAS-reported genes (27.8% of 205 genes) exhibited evidence of differential expression in disease cell-of-origin populations compared to other cell populations at a nominal p-value < 0.05 in at least one stage (Binomial test, P < 0.01 for all). Conclusion: This study reveals the cell-of-origin populations that influence the development of CRC, and provides evidence of the role of risk genes in these populations. These findings are crucial for identifying causal genes and understanding the cellular mechanisms that drive the biology and etiology of CRC. Citation Format: Chao Li, Zhishan Chen, Qing Li, Jungyoon Choi, Quanhu Sheng, Wanqing Wen, Xiang Shu, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Bhuminder Singh, Martha J. Shrubsole, Ken Lau, Wei Zheng, Xingyi Guo. Integrating single-cell RNA-seq and large genome-wide association study data to identify colorectal cancer cell-of-origin populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6614.

Causal relationship between gut microbiota and rosacea: a two-sample Mendelian randomization study.

Rosacea, a chronic inflammatory skin condition affecting millions worldwide, is influenced by complex interactions between genetic and environmental factors. Although gut microbiota's role in skin health is well-acknowledged, definitive causal links between gut microbiota and rosacea remain under-explored. Using a two-sample Mendelian randomization (MR) design, this study examined potential causal relationships between gut microbiota and rosacea. Data was sourced from the largest Genome-Wide Association Study (GWAS) for gut microbiota and the FinnGen biobank for rosacea. A total of 2078 single nucleotide polymorphisms (SNPs) associated with gut microbiota were identified and analyzed using a suite of MR techniques to discern causal effects. The study identified a protective role against rosacea for two bacterial genera: phylum Actinobacteria and genus Butyrivibrio. Furthermore, 14 gut microbiota taxa were discovered to exert significant causal effects on variant categories of rosacea. While none of these results met the strict False Discovery Rate correction threshold, they retained nominal significance. MR outcomes showed no pleiotropy, with homogeneity observed across selected SNPs. Directionality tests pointed toward a robust causative path from gut microbiota to rosacea. This study provides compelling evidence of the gut microbiota's nominal causal influence on rosacea, shedding light on the gut-skin axis's intricacies and offering potential avenues for therapeutic interventions in rosacea management. Further research is warranted to validate these findings and explore their clinical implications.

Abstract 6140: Gene-environment interactions for lifetime water arsenic exposure and bladder cancer risk in the New England Bladder Cancer study

Abstract Environmental arsenic and genetic susceptibility have both been shown to increase bladder cancer risk, yet little is known about their respective interaction. We conducted a gene-environment interaction (GxE) study to characterize lifetime arsenic exposure from drinking water, inherited susceptibility, and bladder cancer risk in the New England Bladder Cancer Study. Exposures were estimated from arsenic measured in water samples collected at home and workplace. We evaluated common single-nucleotide polymorphisms (SNPs) i) from the latest bladder cancer genome-wide association study (n= 28), ii) from candidate gene studies of arsenic or bladder cancer (n= 16 SNPs), and iii) SNPs from a large genome-wide association study of arsenic metabolism (n = 4 SNPs) as potential effect modifiers of the arsenic-bladder cancer relationship. We coded SNPs as the absence or presence of a risk/effect allele for bladder cancer or arsenic metabolism in 2,019 adults (928 bladder cancer cases and 1,091 controls) and arsenic exposures as tertiles. Odds ratios (OR) with 95% confidence intervals (CI) adjusted for age, sex, smoking status, high-risk occupation, and principal components of genetic ancestry were estimated using logistic regression models. P-values for multiplicative interaction were calculated. Out of 48 SNPs, we found evidence of interaction for 7 SNPs at the statistical significance level of P<0.05. Most SNPs involved in GxE interactions are mapped to genomic regions known or suspected to function in arsenic metabolism. For the association between cumulative lifetime water arsenic (mg) and bladder cancer, the strongest evidence of an interaction was with rs1046428 (near GSTZ1 on 14q23); among those with one or two copies of the T risk allele, ORT2vsT1: 1.52, CI: 1.11 - 2.07; ORT3 vsT1: 1.44, CI: 1.05 - 1.98, Pinteraction = 0.01; among those with no risk allele copy, ORT2vsT1: 0.91, CI: 0.62 - 1.35; ORT3 vsT1: 0.97, CI: 0.65 - 1.44. For average daily water arsenic (µg/day), we found evidence of interaction among those with risk allele for rs1801133 (A/A, A/G; MTHFR on 1p36) ORT2 vsT1: 1.70, CI: 1.18 - 2.44; ORT3 vsT1: 1.53, CI: 1.06 - 2.23, Pinteraction = 0.02, in those with no copies of risk allele ORT2vsT1: 0.85, CI: 0.61 - 1.17; ORT3 vsT1: 1.11, CI: 0.79 - 1.54; and rs1801131 (G/G; G/T; MTHFR ) ORT2 vsT1: 1.59, CI: 1.14 - 2.22; ORT3 vsT1: 1.63, CI: 1.16 - 2.29, Pinteraction = 0.01, whereas in those with no risk allele ORT2vsT1: 0.84, CI: 0.59 - 1.19; ORT3 vsT1: 1, CI: 0.69 - 1.44. For 40-year lagged cumulative lifetime water arsenic (mg) and average daily water arsenic (µg/day), we found suggestive interactions with rs2234636 (SLC39A2 on 14q11), and rs1495741 (NAT2 on 8p22). Our study provides evidence of interactions between lifetime arsenic exposure and genetic variants that function in xenobiotic metabolism on bladder cancer occurrence. Citation Format: Hugo Pomares-Millan, Stella Koutros, Nathaniel Rothman, Dalsu Baris, Molly Schwenn, Alison Johnson, Debra T. Silverman, Margaret R. Karagas, Michael N. Passarelli. Gene-environment interactions for lifetime water arsenic exposure and bladder cancer risk in the New England Bladder Cancer study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6140.

Abstract P333: Plasma Proteins, Structural Brain Reserve, and Onset of Alzheimer’s Disease: Proteome-Wide Mendelian Randomization

Introduction: While the emergence of amyloid-clearing treatments for Alzheimer’s disease is promising, the identification of additional therapeutic options for Alzheimer’s disease and related dementia syndromes (AD/ADRD) remains urgent. Plasma proteins represent a class of actionable drug targets AD/ADRD treatment. Yet, the role of the blood proteome in influencing structural brain reserve, and consequently, cognitive performance and the development of AD, remains elusive. Hypothesis: Plasma proteins may causally associate with changes in structural brain reserve and cognition phenotypes. Methods: We conducted proteome-wide Mendelian randomization (MR) to identify potentially causal associations of plasma proteins with changes in brain reserve, proxied by brain imaging-derived phenotypes (IDPs), cognitive performance, and AD onset. Genetic instruments for plasma proteins were previously developed by integrating summary data from five genome-wide association studies (GWASs) of plasma proteome. Summary statistics from large GWASs of 12 AD-associated IDPs (N=33,224), cognitive performance (N=257,841), and two AD cohorts (IGAP consortium, N=63,926, and FinnGen study, N=309,154) are obtained to perform two-sample MR. Causal estimates from two AD outcomes are meta-analyzed to improve statistical power. Correction for multiple testing and sensitivity analyses are performed. Results: Among 956 proteins with genetic instruments that satisfied MR assumptions, genetically determined levels of 14 plasma proteins were associated with at least one of the 10 AD-related IDPs at a false discovery rate of 5%. Six of these proteins were associated with white matter hyperintensities, an IDP known to be involved in cognitive decline. In addition, 26 plasma proteins were associated with cognitive performance, and four were causally linked to AD. Notably, four identified proteins were associated with structural brain reserve and either cognition or AD. Specifically, ADAM12, CREB3L4, and UROS were associated with distinct IDPs and cognitive performance, while TMEM106B, a protein that forms age-dependent amyloid filaments, was associated with increased hippocampal tail volume and AD. Conclusions: This study identified potential causal plasma proteins underlying structural brain reserve, cognitive performance, and AD, offering insights into the molecular etiology of these conditions and potential targets for drug development.

Epilepsy and childhood psychiatric disorders: a two-sample bidirectional Mendelian randomization study.

Observational studies have indicated that psychiatric disorders are the most common comorbidities in pediatric epilepsy. However, the existence and direction of a causal relationship between the two remains controversial. This study aims to investigate the association between common childhood psychiatric disorders and epilepsy using a two-sample, bidirectional Mendelian randomization (MR) approach. Genetic instruments were obtained from the most recent and largest genome-wide association studies (GWAS), including datasets for epilepsy (N_case = 29,994, N_control = 52,538), attention deficit hyperactivity disorder (ADHD) (N_case = 38,691, N_control = 186,843), autism spectrum disorder (ASD) (N_case = 18,381, N_control = 27,969), and Tourette syndrome (TS) (N_case = 4,819, N_control = 9488). MR analyses were conducted using the inverse variance weighted (IVW) method, weighted median method, and MR-Egger regression. No reliable evidence was found to suggest a causal effect of ADHD, ASD, or TS on epilepsy, nor was there any reliable evidence indicating that epilepsy increases the risk of these three psychiatric disorders. These findings remained consistent across various sensitivity analyses. Although observational studies have highlighted a high comorbidity rate between pediatric epilepsy and psychiatric disorders like ADHD and ASD, the MR analysis did not confirm a causal relationship between them. This suggests that previous studies might have been influenced by confounding biases or other biases, potentially overestimating the true relationship. A deeper understanding of the mechanisms underlying these comorbidities is crucial for refining the treatment of pediatric epilepsy.

Analyses of potential causal contributors to increased waist/hip ratio-associated cardiometabolic disease: A combined and sex-stratified Mendelian randomization study.

Increased waist/hip ratio (WHR) contributes to type 2 diabetes, fatty liver, dyslipidaemia, hypertension and coronary artery disease, with potential sex-differential effects. Postulated mediators include increased lipid flux, branched-chain amino acids, glycine and glycoprotein acetyl, but their relative contributions and sex-specific impact on WHR-associated cardiometabolic disease (CMD) are not established. We therefore undertook combined and sex-stratified Mendelian randomization (MR) to assess the relative causal contributions of these mediators to WHR-associated CMD using summary statistics from the largest genome-wide association studies in European ancestries. In sex-combined MR analyses, increased WHR significantly reduces high-density lipoprotein (beta = -0.416, SE = 0.029, p = 2.87E-47), increases triglyceride (beta = 0.431, SE = 0.029, p = 1.87E-50), type 2 diabetes (odds ratio = 2.747, SE = 0.09, p = 26E-23), coronary artery disease (odds ratio = 1.478, SE = 0.045, p = 6.96E-18), alanine transaminase (beta = 0.062, SE = 0.004, p = 6.88E-67), and systolic (beta = 0.134, SE = 0.022, p = 7.81E-10) and diastolic blood pressure (beta = 0.162, SE = 0.026, p = 5.38E-10). Adjustment for the mediators attenuated WHR's effects, but the associations remained significant with concordant results in females. In males, a similar pattern was seen, except after adjusting for the effect of the ratio of monounsaturated fatty acid to total free fatty acid, the potential causal effect of WHR was no longer significant: high-density lipoprotein (beta = -0.117, SE = 0.069, p = .09) and triglyceride (beta = 0.051, SE = 0.068, p = .459). MR suggests WHR increases the risk of CMD independent of these mediators, with the exception of dyslipidaemia in males, which is largely driven by the monounsaturated fatty acid to total free fatty acid ratio.

Novel signals and polygenic score for height are associated with pubertal growth traits in Southwestern American Indians.

Most genetic variants associated with adult height have been identified through large genome-wide association studies (GWASs) in European-ancestry cohorts. However, it is unclear how these variants influence linear growth during adolescence. This study uses anthropometric and genotypic data from a longitudinal study conducted in an American Indian community in Arizona between 1965-2007. Growth parameters (i.e. height, velocity, and timing of growth spurt) were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, in 787 participants with height measurements spanning the whole period of growth. Heritability estimates suggested that genetic factors could explain 25% to 71% of the variance of pubertal growth traits. We performed a GWAS of growth parameters, testing their associations with 5 077 595 imputed or directly genotyped variants. Six variants associated with height at peak velocity (P < 5 × 10-8, adjusted for sex, birth year and principal components). Implicated genes include NUDT3, previously associated with adult height, and PACSIN1. Two novel variants associated with duration of growth spurt (P < 5 × 10-8) in LOC105375344, an uncharacterized gene with unknown function. We finally examined the association of growth parameters with a polygenic score for height derived from 9557 single nucleotide polymorphisms (SNPs) identified in the GIANT meta-analysis for which genotypic data were available for the American Indian study population. Height polygenic score was correlated with the magnitude and velocity of height growth that occurred before and at the peak of the adolescent growth spurt, indicating overlapping genetic architecture, with no influence on the timing of adolescent growth.

Evidence for genetic causality between iron homeostasis and Parkinson's disease: A two-sample Mendelian randomization study

BackgroundParkinson's disease (PD) is a degenerative disease of the central nervous system, and its specific etiology is still unclear. At present, it is believed that the main pathological basis is the reduction of dopamine concentration in the brain striatum. Although many previous studies have believed that iron as an important nutrient element participates in the occurrence and development of PD, whether there is a causal correlation between total iron binding capacity(TIBC), transferring saturation(TSAT), ferritin and serum iron in iron homeostasis indicators and PD, there has been a lack of effective genetic evidence. MethodsWe used Mendelian randomization (MR) as an analytical method to effectively evaluate the genetic association between exposure and outcome, based on the largest genome-wide association study (GWAS) data to date. By using randomly assigned genetic instrumental variables (SNPs, Single Nucleotide Polymorphisms) that are not affected by any causal relationship, we effectively evaluated the causal relationship between iron homeostasis indicators and PD while controlling for confounding factors. ResultsBy coordinated analysis of 86 SNPs associated with iron homeostasis markers and 12,858,066 SNPs associated with PD, a total of 56 SNPs were finally screened for genome-wide significance of iron homeostasis associated with PD. The results of inverse variance weighting(IVW) analysis suggested that iron（ β = - 0.524; 95%cl=-0.046 to −0.002; P=0.032) was considered to have a genetic causal relationship with PD. Cochran's Q, Egger intercept and MR-PRESSO global tests did not detect the existence of heterogeneity and pleiotropy (P>0.05). Mr Steiger directionality test further confirmed our estimation of the potential causal direction of iron and PD (P=0.001). In addition, TIBC (β=-0.142; 95%Cl=-0.197–0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861–0.229; P=0.255), and ferritin (β=-0.387; 95%Cl=-1.179–0.405; P=0.338) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). In addition, TIBC (β=-0.142; 95%Cl=-0.197–0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861–0.229; P=0.255), and ferritin (β=-0.101; 95%Cl=--0.987 to −0.405; P=0.823) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). TIBC (P=0.008), TSAT (P=0.000) and ferritin (P=0.013) were all consistent with the estimation of MR Steiger directivity test. ConclusionOur study found that among the four iron homeostasis markers, there was a genetic causal association between serum iron and PD, and the serum iron level was negatively correlated with the risk of PD. In addition, TIBC, TSAT, ferritin had no genetic causal relationship with PD.

Causal effects of childhood obesity on neuroticism and subjective well-being: A two-sample Mendelian randomization study

BackgroundChildhood obesity is linked to both neuroticism and subjective wellbeing (SWB); however, the causal relations between them remain unclear. MethodsTwo-sample Mendelian randomization (MR) analysis was applied to determine the causal effects of childhood BMI (n = 39,620) on neuroticism (n = 366,301) and SWB (n = 298,420) using summary statistics from large scale genome-wide association studies (GWASs). Inverse-variance weighting (IVW), weighted mode, weighted median, and MR-Egger approaches were used to estimate the causal effects. Sensitivity analyses including the Cochran's Q statistics, MR-Egger intercept test, MR-PRESSO global test, and the leave-one-out (LOO) analysis were used to assess potential heterogeneity and horizontal pleiotropy. Two-step MR mediation analysis was employed to explore the potential mediation effects of neuroticism on the causal relationship between childhood BMI and SWB. ResultsOur study revealed that genetically predicted higher childhood BMI was causally associated with increased neuroticism (beta = 0.045, 95%CI = 0.013,0.077, p = 6.066e-03) and reduced SWB (beta = −0.059, 95%CI = -0.093,-0.024, p = 9.585e-04). Sensitivity analyses didn't detect any significant heterogeneity and horizontal pleiotropy (all p > 0.05). Additionally, the two-step MR mediation analysis indicated that the causal relationship between childhood BMI and SWB was partially mediated by neuroticism (proportion of mediation effects in total effects: 21.3 %, 95%CI: 5.4 % to 37.2, p = 0.0088). ConclusionGenetically proxy for higher childhood BMI was associated with increased neuroticism and reduced SWB. Further studies were warranted to investigate the underlying molecular mechanisms and potential use of weight management for improving personality and SWB.

Dissecting the causal relationship between neuroticism and osteoarthritis: a univariable and multivariable Mendelian randomization study.

Mental health has been found to be associated with risk of osteoarthritis (OA), but the causal relationship was not fully clarified. Two-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between neuroticism (n = 329,821) and the two most frequently affected parts of osteoarthritis (OA) (knee OA: case/control =24,955/378,169; hip OA: case/control = 15,704/378,169) using large scale summary genome-wide association study (GWAS) data. Inverse variance weighted (IVW), weighted median, and MR-Egger were used to estimate the causal effects. Multiple sensitivity analyses were conducted to examine the robustness of the causal estimates. Multivariable MR analysis was used to estimate the direct effects of neuroticism on OA after accounting for the other OA risk factors. Two-step MR approach was employed to explore the potential mediators of the causal relationship. Univariable MR analysis indicated that 1-SD increase in genetically predicted neuroticism score was associated with an increased risk of knee OA (IVW: OR, 1.17; 95% CI, 1.087-1.26; p = 2.72E-05) but not with hip OA. The causal effects remained significant after accounting for the effects of BMI, alcohol drinking, and vigorous physical activity but were attenuated with adjustment of smoking. Further mediation analysis revealed that smoking initiation mediated a significant proportion of the causal effects of neuroticism on knee OA (proportion of mediation effects in total effects: 22.3%; 95% CI, 5.9%-38.6%; p = 7.60E-03). Neuroticism has significant causal effects on knee OA risk. Smoking might partly mediate the causal relationship. Further studies were warranted to explore the underlying mechanisms and potential use of neuroticism management for OA treatment.

A genetic risk score to predict treatment nonresponse in psychotic depression

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = −0.32, p = 0.0023, n = 88) and remission (r = −0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.

Evaluating the causal effect of atherosclerosis on the risk of intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) and atherosclerosis are two common age-related conditions that can cause significant morbidity. While previous studies have suggested an association between the two conditions, the nature of this association remains unclear. We used Mendelian randomization (MR) to investigate the causal relationship between IDD and atherosclerosis. We identified genetic variants associated with IDD using summary statistics from a large genome-wide association study (GWAS). These variants were then used as instrumental variables to infer causal relationships with atherosclerosis in summary statistics from a separate GWAS. Our MR analysis provided evidence for a causal relationship between IDD and atherosclerosis. We found that the genetic predisposition to atherosclerosis was associated with a higher risk of IDD (odds ratio [OR] = 3.55, 95% confidence interval [CI]: 1.07-11.74, p = 0.04). The IVW estimates were consistent with the observational findings and other robust MR methods. Sensitivity analyses suggested that our findings were robust to potential sources of bias. Our study provides evidence for a causal link between IDD and atherosclerosis, suggesting that interventions targeting atherosclerosis could have potential benefits for reducing the risk of IDD. Further research is needed to explore the underlying mechanisms that link these two conditions and to investigate potential therapeutic interventions.

Levels of 91 circulating inflammatory proteins and risk of lumbar spine and pelvic fractures and peripheral ligament injuries: a two-sample mendelian randomization study

ObjectiveLumbar spine and pelvic fractures(LPF) are combined with peripheral ligament injuries(PLI), frequently. It has been reported that the site of fracture injury is usually paralleled by the secretion of inflammatory proteins. This study aimed to investigate the causal relationship between 91 circulating inflammatory proteins and LPF and PLI by using a Two-sample Mendelian randomization (MR) analysis.MethodsSingle nucleotide polymorphisms (SNPs) associated with 91 circulating inflammatory proteins, as exposures were selected from a large genome-wide association study (GWAS). The genetic variant data for LPF and PLI as outcomes from the FinnGen consortium. The inverse-variance-weighted (IVW) method was utilized as the main analysis for exposures and outcomes. In addition, the final results were reinforced by the methods of MR Egger, weighted median, simple mode, and weighted mode. The sensitivity analyses were used to validate the robustness of results and ensure the absence of heterogeneity and horizontal pleiotropy. MR-Steiger was used to assess whether the causal direction was correct to avoid reverse causality.ResultsThis study has shown that Beta-nerve growth factor(Beta-NGF) and Interferon gamma(IFN-gamma) are both involved in the occurrence of LPF and PLI, and they are reducing the risk of occurrence(OR:0.800, 95%CI: 0.650–0.983; OR:0.723, 95%CI:0.568–0.920 and OR:0.812, 95%CI:0.703–0.937; OR:0.828, 95%CI:0.700–0.980). Similarly, Axin-1 and Sulfotransferase 1A1 (SULT-1A1) were causally associated with LPF(OR:0.687, 95%CI:0.501–0.942 and OR:1.178,95%CI:1.010–1.373). Furthermore, Interleukin-4(IL-4), Macrophage inflammatory protein 1a(MIP-1a), and STAM binding protein(STAM-BP) were causally associated with PLI(OR:1.236, 95% CI: 1.058–1.443; OR:1.107, 95% CI: 1.008–1.214 and OR:0.759, 95% CI: 0.617–0.933). The influence of heterogeneity and horizontal pleiotropy were further excluded by sensitivity analysis.ConclusionThis study provides new insights into the relationship between circulating inflammatory proteins and LPF and PLI, and may provide new clues for predicting this risk.