Nominal Association Research Articles

Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aβ) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.

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...

Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population.

Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

Mitochondrial haplogroup R offers protection against obesity in Kuwaiti and Qatari populations.

The Kuwaiti and Qatari populations have a high prevalence of obesity, a major risk factor for various metabolic disorders. Previous studies have independently explored mitochondrial DNA (mtDNA) variations and their association with obesity in these populations. This study aims to investigate the role of mtDNA haplogroups and variants in obesity risk among these Gulf populations. Whole exome sequencing data from 1,112 participants (348 Kuwaitis and 764 Qataris) were analyzed for mtDNA variants. Participants were classified as obese or non-obese based on body mass index (BMI). Association analyses were performed to examine the relationship between mtDNA haplogroups and obesity, adjusting for covariates such as age and sex. Haplogroup R was found to be protective against obesity, with an odds ratio (OR) of 0.69 (p = 0.045). This association remained significant after adjusting for age and sex (OR = 0.694; 95% CI: 0.482-0.997; p = 0.048). Several mtDNA variants, particularly those involved in mitochondrial energy metabolism, showed nominal associations with obesity, but these did not remain significant after correcting for multiple testing. Haplogroup R consistently demonstrates a protective association against obesity in both Kuwaiti and Qatari populations, highlighting its potential as a biomarker for obesity risk in the Gulf region. However, further research with larger sample sizes is needed to validate these findings and clarify the role of mtDNA variants in obesity.

Genetic Associations of Persistent Opioid Use After Surgery Point to OPRM1 but Not Other Opioid-Related Loci as the Main Driver of Opioid Use Disorder.

Persistent opioid use after surgery is a common morbidity outcome associated with subsequent opioid use disorder, overdose, and death. While phenotypic associations have been described, genetic associations remain unidentified. Here, we conducted the largest genetic study of persistent opioid use after surgery, comprising ~40,000 non-Hispanic, European-ancestry Michigan Genomics Initiative participants (3198 cases and 36,321 surgically exposed controls). Our study primarily focused on the reproducibility and reliability of 72 genetic studies of opioid use disorder phenotypes. Nominal associations (p < 0.05) occurred at 12 of 80 unique (r2 < 0.8) signals from these studies. Six occurred in OPRM1 (most significant: rs79704991-T, OR = 1.17, p = 8.7 × 10-5), with two surviving multiple testing correction. Other associations were rs640561-LRRIQ3 (p = 0.015), rs4680-COMT (p = 0.016), rs9478495 (p = 0.017, intergenic), rs10886472-GRK5 (p = 0.028), rs9291211-SLC30A9/BEND4 (p = 0.043), and rs112068658-KCNN1 (p = 0.048). Two highly referenced genes, OPRD1 and DRD2/ANKK1, had no signals in MGI. Associations at previously identified OPRM1 variants suggest common biology between persistent opioid use and opioid use disorder, further demonstrating connections between opioid dependence and addiction phenotypes. Lack of significant associations at other variants challenges previous studies' reliability.

Exploring causal associations of antioxidants from supplements and diet with attention deficit/hyperactivity disorder in European populations: a Mendelian randomization analysis.

Antioxidants from both supplements and diet have been suggested to potentially reduce oxidative stress in individuals with ADHD. However, there is a lack of studies utilizing the Mendelian randomization (MR) method to explore the relationship between dietary and supplemental antioxidants with ADHD. This study employed two-sample mendelian randomization. Various specific antioxidant dietary supplements (such as coffee, green tea, herbal tea, standard tea, and red wine intake per week), along with diet-derived circulating antioxidants including Vitamin C (ascorbate), Vitamin E (α-tocopherol), Vitamin E (γ-tocopherol), carotene, Vitamin A (retinol), zinc, and selenium (N = 2,603-428,860), were linked to independent single nucleotide polymorphisms (SNPs). Data on ADHD was gathered from six sources, comprising 246,888 participants. The primary analytical method utilized was inverse variance weighting (IVW), with sensitivity analysis conducted to assess the robustness of the main findings. In different diagnostic periods for ADHD, we found that only green tea intake among the antioxidants was significantly associated with a reduced risk of ADHD in males (OR: 0.977, CI: 0.963-0.990, p < 0.001, FDR = 0.065), with no evidence of pleiotropy or heterogeneity observed in the results. Additionally, a nominal causal association was found between green tea intake and childhood ADHD (OR: 0.989, 95% CI: 0.979-0.998, p = 0.023, FDR = 0.843). No causal relationships were detected between the intake of other antioxidant-rich diets and ADHD. Our study found a significant inverse association between green tea intake and male ADHD, suggesting that higher green tea consumption may reduce ADHD risk in males. Further research is needed to explore optimal doses and underlying mechanisms.

Phenome-Wide Association Study of Latent Autoimmune Diabetes from a Southern Mexican Population Implicates rs7305229 with Plasmatic Anti-Glutamic Acid Decarboxylase Autoantibody (GADA) Levels.

Latent autoimmune diabetes in adults (LADA) is characterized by the presence of glutamate decarboxylase autoantibodies (GADA). LADA has intermediate features between type 1 diabetes and type 2 diabetes. In addition, genetic risk factors for both types of diabetes are present in LADA. Nonetheless, evidence about the genetics of LADA in non-European populations is scarce. This study aims to perform a genome-wide association study with a phenome-wide association study of LADA in a southeastern Mexican population. We included 59 patients diagnosed with LADA from a previous study and 3121 individuals without diabetes from the MxGDAR/ENCODAT database. We utilized the GENESIS package in R to perform the genome-wide association study (GWAS) of LADA and PLINK for the phenome-wide association study (PheWAS) of LADA features. Nine polymorphisms reach the nominal association level (1 × 10-5) in the GWAS. The PheWAS showed that rs7305229 is genome-wide and associated with serum GADA levels in our sample (p = 1.84 × 10-8). rs7305229 is located downstream of the FAIM2 gene; previous reports associate FAIM2 variants with childhood obesity, body mass index, body adiposity measures, lymphocyte CD8+ activity, and anti-thyroid peroxidase antibodies. Our findings reveal that rs7305229 affects the GADA levels in patients with LADA from southeastern Mexico. More studies are needed to determine if this risk genotype exists in other populations with LADA.

The impact of genetic variations in the serotonergic system on symptom severity and clinical outcome in functional neurological disorders

ObjectiveWe studied gene-environment, as well as gene-gene interaction to elucidate their effects on symptom severity and predict clinical outcomes in functional neurological disorders (FND). MethodsEighty-five patients with mixed FND were genotyped for ten single-nucleotide polymorphisms (SNP) from seven different stress-related genes. We tested cross-sectionally the association between genotype and the symptomatology of FND (symptom severity assessed with the examiner-based clinical global impression score [CGI] and age of onset). Clinical outcome was assessed in 52 patients who participated in a follow-up clinical visit after eight months (following their individual therapies as usual). We tested longitudinally the association between genotype and clinical outcome in FND. We examined the contribution of each SNP and their interaction between them to FND symptomatology and outcome. ResultsWe identified a nominal association between tryptophan hydroxylase 1 (TPH1) rs1800532 and symptom severity (CGI1) in FND under a codominant model (T/T: ßT/T = 2.31, seT/T = 0.57; G/T: ßG/T = -0.18, seG/T = 0.29, P = 0.035), with minor allele (T) carriers presenting more severe symptoms. An association was identified between TPH1 and clinical outcome, suggesting that major allele (G) carriers were more likely to have an improved outcome under a codominant model (G/T: ORG/T = 0.18, CIG/T = [0.02–1.34]; T/T: ORT/T = 2.08, CIT/T = [0.30–14.53], P = 0.041). Our analyses suggested a significant gene-gene interaction for TPH2 (rs4570625) and OXTR (rs2254298) on symptom severity, and a significant gene-gene interaction for TPH1, TPH2 and BDNF (rs1491850) on clinical outcome. ConclusionFND might arise from a complex interplay between individual predisposing risk genes involved in the serotonergic pathway and their gene-gene interactions.

Mapping prenatal predictors and neurobehavioral outcomes of an epigenetic marker of neonatal inflammation – A longitudinal population-based study

BackgroundDNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for − or offspring outcomes of − elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population. MethodsOur study was embedded in the prospective population-based Generation R Study (n = 2,394). We created a methylation profile score of CRP (MPS-CRP) in cord blood as a marker of neonatal inflammation and validated it against serum CRP levels in mothers during pregnancy, as well as offspring at birth and in childhood. We then examined (i) which factors (previously associated with sustained inflammation) explain variability in MPS-CRP at birth, including a wide range of prenatal lifestyle and clinical conditions, pro-inflammatory exposures, as well as child genetic liability to elevated CRP levels; and (ii) whether MPS-CRP at birth associates with child neurobehavioral outcomes, including global structural MRI and DTI measures (child mean age 10 and 14 years) as well as psychiatric symptoms over time (Child Behavioral Checklist, at mean age 1.5, 3, 6, 10 and 14 years). ResultsMPS-CRP at birth was validated with serum CRP in cord blood (cut-off > 1 mg/L) (AUC = 0.72). Prenatal lifestyle pro-inflammatory factors explained a small part (i.e., < 5%) of the variance in the MPS-CRP at birth. No other prenatal predictor or the polygenic score of CRP in the child explained significant variance in the MPS-CRP at birth. The MPS-CRP at birth prospectively associated with a reduction in global fractional anisotropy over time on mainly a nominal threshold (β = -0.014, SE = 0.007, p = 0.032), as well as showing nominal associations with structural differences (amygdala [(β = 0.016, SE = 0.006, p = 0.010], cerebellum [(β = -0.007, SE = 0.003, p = 0.036]). However, no associations with child psychiatric symptoms were observed. ConclusionPrenatal exposure to lifestyle-related pro-inflammatory factors was the only prenatal predictor that accounted for some of the individual variability in MPS-CRP levels at birth. Further, while the MPS-CRP prospectively associated with white matter alterations over time, no associations were observed at the behavioral level. Thus, the relevance and potential utility of using epigenetic data as a marker of neonatal inflammation in the general population remain unclear. In the future, the use of epigenetic proxies for a wider range of immune markers may lend further insights into the relationship between neonatal inflammation and adverse neurodevelopment within the general pediatric population.

RNA-DNA differences in variant calls from cattle tissues result in erroneous eQTLs

BackgroundAssociation testing between molecular phenotypes and genomic variants can help to understand how genotype affects phenotype. RNA sequencing provides access to molecular phenotypes such as gene expression and alternative splicing while DNA sequencing or microarray genotyping are the prevailing options to obtain genomic variants.ResultsWe genotype variants for 74 male Braunvieh cattle from both DNA (~ 13-fold coverage) and deep total RNA sequencing from testis, vas deferens, and epididymis tissue (~ 250 million reads per tissue). We show that RNA sequencing can be used to identify approximately 40% of variants (7–10 million) called from DNA sequencing, with over 80% precision. Within highly expressed coding regions, over 92% of expected variants were called with nearly 98% precision. Allele-specific expression and putative post-transcriptional modifications negatively impact variant genotyping accuracy from RNA sequencing and contribute to RNA-DNA differences. Variants called from RNA sequencing detect roughly 75% of eGenes identified using variants called from DNA sequencing, demonstrating a nearly 2-fold enrichment of eQTL variants. We observe a moderate-to-strong correlation in nominal association p-values (Spearman ρ2 ~ 0.6), although only 9% of eGenes have the same top associated variant.ConclusionsWe find hundreds of thousands of RNA-DNA differences in variants called from RNA and DNA sequencing on the same individuals. We identify several highly significant eQTL when using RNA sequencing variant genotypes which are not found with DNA sequencing variant genotypes, suggesting that using RNA sequencing variant genotypes for association testing results in an increased number of false positives. Our findings demonstrate that caution must be exercised beyond filtering for variant quality or imputation accuracy when analysing or imputing variants called from RNA sequencing.

Association of peripheral inflammatory indicators with osteoarthritis risk

ObjectivesNumerous studies have established the role of inflammation in osteoarthritis (OA) progression, yet limited research explores the association between systemic inflammatory indicators and pre-diagnosis OA risk. This study aimed to investigate the association between peripheral inflammatory indicators and the risk of OA using data from the UK Biobank. MethodsThe study analyzed data from 417,507 participants in the UK Biobank, including neutrophil count, lymphocyte count, monocyte count, platelet count, and C-reactive protein meter. Additionally, derived ratios such as NLR(neutrophils-lymphocytes ratio), PLR(Platelets-lymphocytes ratio), SII(systemic immune-inflammation index), and LMR (lymphocytes-monocytes ratio) were examined. Cox proportional hazards models and restricted cubic spline models were used to assess both linear and nonlinear associations. ResultsOver a mean follow-up period of 12.7 years, a total of 49,509 OA events were identified. The findings revealed that CRP (HR:1.06, 95%CI:1.05–1.07), NLR (HR:1.02, 95%CI:1.01–1.03), PLR (HR:1.02, 95%CI:1.01–1.03), and SII (HR:1.03, 95%CI:1.01–1.04) were associated with an increased risk of OA, while LMR (HR:0.97, 95%CI:0.96–0.99) showed a significant negative correlation with OA risk. Subgroup analyses further emphasized that these associations were significant across most of the population. Although neutrophils, lymphocytes, monocytes, and platelets showed a nominal association with the risk of OA, the results were unreliable, especially for specific joint OA. ConclusionThe study provides evidence of a significant association between elevated peripheral inflammatory indicators and OA risk. These findings underscore the importance of low-grade chronic inflammation in OA development. The potential clinical utility of these indicators as early predictors of OA is suggested, warranting further exploration.

Genetic causal relationship between multiple immune cell phenotypes and Parkinson's disease: a two-sample bidirectional Mendelian randomization study.

The exact etiology of Parkinson's disease (PD), a degenerative disease of the central nervous system, is unclear. It is currently believed that its main pathological basis is a decrease in dopamine concentration in the striatum of the brain. Although many researchers have previously focused on the critical role of the immune response in PD, there has been a lack of valid genetic evidence for a causal association between specific immune cell traits and phenotypes and PD. We employed Mendelian randomization (MR) as an analytical method to effectively assess genetic associations between exposure and outcome. Based on the largest Genome-Wide Association Study (GWAS) dataset to date, causal associations between multiple immune cell phenotypes and PD were validly assessed, controlling for confounding factors by using single-nucleotide polymorphisms (SNPs), which are genetic instrumental variables that are randomly assigned and not subject to any causality. By testing 731 immune cell phenotypes and their association with PD, the results of inverse variance weighting (IVW) analysis suggested that after Bonferroni correction multiple immune cell phenotypes had no statistically significant effect on PD. It is worth mentioning that some phenotypes with unadjusted P values (P < 0.05), including 40 immune phenotypes, that were located on the cDC panel, the Treg panel, the Maturation stages of T cell panel, the TBNK panel, the B cell panel, the Myeloid cell panel, and the Monocyte panel were considered to have nominal associations with PD. In addition, PD could have an effect on certain immunophenotypes located on the Myeloid cell panel and the Monocyte panel; the specific immunophenotypic results and statistical analysis values are shown in the text. The results of sensitivity analyses suggested that none of these observed the presence of horizontal pleiotropy. Our study identified a close link between immune cells and PD, and the results of this study provide ideas for the study of the immune mechanism of PD and the exploration of effective therapeutic means.NEW & NOTEWORTHY In this study, based on the GWAS Immunophenotyping Database, a Mendelian randomization approach was used to assess the genetic causal associations between 731 immunophenotypes and traits and Parkinson's disease (PD), which not only provides a reference for the immune response mechanism of PD but also provides ideas for exploring the effective diagnosis and treatment of PD.

HLA associations with immunotherapy related endocrine toxicity.

2516 Background: Endocrine immune related adverse events (irAEs), including thyroid dysfunction (ICI-T), diabetes mellitus (ICI-DM) and hypophysitis (ICI-HP), caused by treatment with immune checkpoint inhibitors (ICIs) are largely irreversible and pose a burden to cancer patients. Variation in HLA predisposes to many autoimmune conditions, but data associating endocrine irAEs to HLA types is limited. Methods: We included 6300 patients from multiple centers across the United States, Canada, Europe and Australia who were treated with ICIs for multiple cancer types. The most common endocrine irAE in these patients was ICI-T (806 cases), followed by ICI-HP (163 cases) and ICI-DM (75 cases). Cases of ICI induced adrenal insufficiency were considered to be ICI-HP unless the patient had an elevated ACTH. Patients without the specific irAE were considered controls. Genotyping and HLA imputation were completed at each institution independently. Associations between HLA types and ICI-T, ICI-DM, and ICI-HP were tested in patients of European ancestry after adjustment for type of immunotherapy (PD-1/PD-L1 monotherapy, anti-CTLA-4 monotherapy, and combination), cancer type, sex, age and 5 principal components, at each center. The results were then meta-analyzed using fixed-effects inverse-variance weighted approach. False discovery rate (FDR) adjusted p-value of 0.05 was considered significant whereas those between 0.05 and 0.1 were considered nominally significant. Results: In the ICI-DM group, we identified 1 significant association with HLA DRB1*04:01 (OR=2.45, FDR=0.002) which is known to increase risk for type 1 DM (T1DM) in European ancestry. There were 5 additional nominal associations including DRB1*0301 (OR=2.16, FDR=0.07), a known HLA for T1DM in European ancestry. For ICI-HP, there were 7 significantly associated HLA types. Of particular interest are DRB1*14:01 (OR=3.98, FDR=0.02), DRB1*07:01 (OR=1.86, FDR=0.02) and C*07:02 haplotype (OR=1.79, FDR=0.02). While DR7 and DR14 are novel associations, C*07:02 is in linkage disequilibrium with DR15 and DQB1*06:02, both of which have previously been associated with ICI-HP. For ICI-T, there were no associated HLA types. Conclusions: In our study, we report HLA types associated with endocrine irAEs. In particular, we see HLA associations for ICI-DM that are known to be associated with T1DM. This suggests a potential shared mechanism between these forms of autoimmune DM. Additionally we found novel HLA associations with ICI-HP. These findings may have an impact on the clinical care of patients treated with ICI. However, further work is warranted to determine if HLA typing prior to ICI initiation should be considered for irAE risk prediction, irAE surveillance, irAE prevention, and possibly cancer treatment decisions.

Genetic association of TIE2 with diabetic retinopathy and diabetic macular edema

PurposeTo evaluate the associations of the TIE2 gene with diabetic retinopathy (DR) and diabetic macular edema (DME). MethodsThis study included a Chinese cohort of 285 non-proliferative DR patients and 433 healthy controls. The DR patients were classified further into those with or without DME. Thirty haplotype-tagging single-nucleotide polymorphisms (SNPs) in TIE2 were genotyped using TaqMan technology. Associations of DR and subtypes were analyzed by logistic regression adjusted for age and sex. Stratification association analysis by sex was performed. ResultsTIE2 rs625767 showed a nominal but consistent association with DR [odds ratio (OR) = 0.71, P = 0.005] and subtypes (DR without DME: OR = 0.69, P = 0.016; DME: OR = 0.73, P = 0.045). SNP rs652010 was consistently associated with overall DR (OR = 0.74, P = 0.011) and DR without DME (OR = 0.70, P = 0.016), but not with DME. Moreover, SNPs rs669441, rs10967760, rs549099 and rs639225 showed associations with overall DR, whilst rs17761403, rs664461 and rs1413825 with DR without DME. In stratification analysis, three SNPs, rs625767 (OR = 0.62, P = 0.005), rs669441 (OR = 0.63, P = 0.006) and rs652010 (OR = 0.64, P = 0.007), were associated with DR in females, but not in males. Moreover, one haplotype T-T defined by rs625767 and rs669441 was significantly associated with DR in females only. ConclusionsThis study revealed TIE2 as a susceptibility gene for DR and DME in Chinese, with a sex-specific association in females. Further validation should be warranted.

Abstract 6139: Genetic modifiers of KRAS-mutant colorectal cancer

Abstract Somatic driver mutations in KRAS are found in ~40% of colorectal cancers (CRCs) and are associated with worse outcomes. In the US, individuals of African ancestry with CRC are more likely to have tumors with KRAS mutations than individuals of European ancestry, even after considering differences in socioeconomic status and other risk factors. Germline variants can influence somatic mutation events and may provide a selective advantage such that a mutated cell is more likely to progress to a cancer. Germline variants have been found to associate with somatic mutations in a variety of tumors. Based on ancestry differences in KRAS tumor mutation frequency, we hypothesized that germline variants altering molecular pathways that support KRAS tumorigenesis will associate with KRAS-mutant status. To test this, we performed a two-step association study using KRAS mutation status as our phenotype in individuals with microsatellite stable CRC. First, we conducted a discovery analysis using genome-wide germline genotypes and somatic mutation data from 6,386 non-Hispanic White CRC patients from the Cancer Genome Atlas and the GECCO consortium, considering sex and tumor location as covariates. To select variants for additional study, we used in-silico tools, such as expression quantitative trait loci (eQTL), to predict how associated variants may alter gene expression and chromatin. After reviewing relevant genomic features, excluding SNVs with minor allele frequency &amp;lt;10% and pruning SNVs in linkage disequilibrium (r2&amp;gt;0.75), we identified candidate loci for a multi-ancestry independent validation analysis. In the discovery analysis, no variants met genome-wide significance thresholds (p-value &amp;lt;5x10-8), though 3 SNVs associated with KRAS mutation status with p-values &amp;lt;1x10-6 and 50 with p-values &amp;lt;1x10-5. Of these 50 SNVs, 21 met criteria for validation. We chose 80 additional SNVs (p-value &amp;lt;1x10-4) with predicted functional effect, for a total of 101 SNVs for analyses. In our preliminary validation analysis of 1,487 individuals grouped by self-reported race, no variants had a significant association in all populations. The rs726800 variant showed nominal association with KRAS mutation status (p-value=0.028) in self-reported non-Hispanic White individuals. This variant is within potential cis-regulatory distance of HS3ST3A1 and COX10-DT, both of which have been reported as cancer biomarkers. Nominal associations were identified in self-reported Black (n=7 SNVs) and Hispanic or Latino (n=3 SNVs) individuals, though both groups had limited sample sizes. Additional validation samples are being analyzed, as well as analysis with adjustment for genetic ancestry. Future functional studies of top candidate variants will add mechanistic insight. In summary, we identified germline SNVs that associate with KRAS somatic mutations in CRC and may inform the cellular context that supports development of colorectal tumors with KRAS mutations. Citation Format: Nijole P. Tjader, Johnny Ramroop, Tanish Gandhi, Peter T. Campbell, Andrew T. Chan, Steven Gallinger, Graham G. Giles, Marc J. Gunter, Tabitha A. Harrison, Michael Hoffmeister, Polly A. Newcomb, Shuji Ogino, Amanda I. Phipps, Conghui Qu, Robert E. Schoen, Andrew Pellatt, Michael O. Woods, Bethany Van Guelpen, Patrick Stevens, Heather Hampel, Ulrike Peters, Joseph P. McElroy, Amanda E. Toland. Genetic modifiers of KRAS-mutant colorectal cancer [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 6139.

Causal association of gut microbiota on spondyloarthritis and its subtypes: a Mendelian randomization analysis.

Despite establishing an association between gut microbiota and spondyloarthritis (SpA) subtypes, the causal relationship between them remains unclear. Gut microbiota data were obtained from the MiBioGen collaboration, and SpA genome-wide association study (GWAS) summary data were obtained from the FinnGen collaboration. We conducted a two-sample Mendelian randomization (MR) analysis using the inverse-variance-weighted method supplemented with four additional MR methods (MR-Egger, weighted median, simple mode, and weighted mode). Pleiotropy and heterogeneity were also assessed. Reverse MR analysis was used to detect reverse causal relationships. We identified 23 causal links between specific gut microbiota taxa and SpA levels. Of these, 22 displayed nominal causal associations, and only one demonstrated a robust causal connection. Actinobacteria id.419 increased the risk of ankylosing spondylitis (AS) (odds ratio (OR) = 1.86 (95% confidence interval (CI): 1.29-2.69); p = 8.63E-04). The family Rikenellaceae id.967 was associated with a reduced risk of both AS (OR = 0.66 (95% CI: 0.47-0.93); p = 1.81E-02) and psoriatic arthritis (OR = 0.70 (95% CI: 0.50-0.97); p = 3.00E-02). Bacillales id.1674 increased the risk of AS (OR = 1.23 (95% CI: 1.00-1.51); p = 4.94E-02) and decreased the risk of enteropathic arthritis (OR = 0.56 (95% CI: 0.35-0.88); p = 1.14E-02). Directional pleiotropy, or heterogeneity, was not observed. No reverse causal associations were observed between the diseases and the gut microbiota. Our MR analysis suggested a genetic-level causal relationship between specific gut microbiota and SpA, providing insights into the underlying mechanisms behind SpA development mediated by gut microbiota.

Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk.

We aimed to characterize genetic correlations and causal associations between circulating C-reactive protein (CRP) levels and the risk of lung cancer (LC). Leveraging summary statistics from genome-wide association studies of circulating CRP levels among 575,531 individuals of European ancestry, and LC risk among 29,266 cases and 56,450 controls, we investigated genetic associations of circulating CRP levels with the risk of overall lung cancer and its histological subtypes, by using linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analyses. Significant positive genetic correlations between circulating CRP levels and the risk of LC and its histological subtypes were identified from LDSC regression, with correlation coefficients ranging from 0.12 to 0.26, and all false discovery adjusted p < 0.05. Univariable MR demonstrated a nominal association between CRP levels and an increased risk of lung squamous cell carcinoma (SCC) (inverse variance-weighted OR = 1.15, 95% CI 1.01-1.30). However, this association disappeared when multivariable MR included cigarettes per day and/or body mass index. By using our recently developed constrained maximum likelihood-based MR method, we identified significant associations of CRP levels with the risk of overall LC (OR 1.06, 95% CI 1.03-1.09), SCC (OR 1.06, 95% CI 1.02-1.09), and small cell lung cancer (SCLC, OR 1.09, 95% CI 1.03-1.15). Moreover, most univariable and multivariable MR analyses also revealed consistent CRP-SCLC associations. There may be a genetic and causal association between circulating CRP levels and the risk of SCLC, which is in line with previous population-based observational studies.

Gut microbiota does not play a mediating role in the causal association between inflammatory bowel disease and several its associated extraintestinal manifestations: a Mendelian randomization study.

Observational study has found inflammatory bowel disease to be associated with multiple extraintestinal manifestations. To this end, we characterized the causal association between inflammatory bowel disease and extraintestinal manifestations through a Mendelian randomization study and further explored the role of intestinal flora in inflammatory bowel disease and the extraintestinal manifestations associated with it. We genetically predicted the causal relationship between inflammatory bowel disease and twenty IBD-related extraintestinal manifestations (including sarcoidosis, iridocyclitis, interstitial lung disease, atopic dermatitis, ankylosing spondylitis, psoriatic arthropathies, primary sclerosing cholangitis, primary biliary cholangitis). We used the full genome-wide association study (GWAS) summary statistics on gut microbiota in 18,340 participants from 24 cohorts to explore its role in the casual relationships between IBD and IBD-related extraintestinal manifestations. Inverse variance weighting (IVW) was used as the main analytical method to assess the causal associations. We performed Cochran's Q test to examine the heterogeneity. To assess the robustness of the IVW results, we further performed sensitivity analyses including the weighted median method, MR-Egger regression, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. The leave-one-out sensitivity analysis was further performed to monitor if significant associations were dominated by a single nucleotide polymorphism (SNP). A total of eight extraintestinal manifestations were found to be at elevated risk of development due to inflammatory bowel diseases. A total of 11 causal relationships were found between IBD and gut microbiota, four of which were stable. Between gut microbiota and these eight extraintestinal manifestations, a total of 67 nominal causal associations were identified, of which 13 associations were stable, and notably 4 associations were strongly correlated. Through the two-sample MR analysis, we identified extraintestinal manifestations that were causally associated with inflammatory bowel disease and obtained multiple associations from inflammatory bowel disease and gut microbiota, and gut microbiota and extraintestinal manifestations in further analyses. These associations may provide useful biomarkers and potential targets for pathogenesis and treatment.

Genetically predicted causality between gut microbiota, blood metabolites, and intracerebral hemorrhage: a bidirectional Mendelian randomization study.

Recent research linked changes in the gut microbiota and serum metabolite concentrations to intracerebral hemorrhage (ICH). However, the potential causal relationship remained unclear. Therefore, the current study aims to estimate the effects of genetically predicted causality between gut microbiota, serum metabolites, and ICH. Summary data from genome-wide association studies (GWAS) of gut microbiota, serum metabolites, and ICH were obtained separately. Gut microbiota GWAS (N = 18,340) were acquired from the MiBioGen study, serum metabolites GWAS (N = 7,824) from the TwinsUK and KORA studies, and GWAS summary-level data for ICH from the FinnGen R9 (ICH, 3,749 cases; 339,914 controls). A two-sample Mendelian randomization (MR) study was conducted to explore the causal effects between gut microbiota, serum metabolites, and ICH. The random-effects inverse variance-weighted (IVW) MR analyses were performed as the primary results, together with a series of sensitivity analyses to assess the robustness of the results. Besides, a reverse MR was conducted to evaluate the possibility of reverse causation. To validate the relevant findings, we further selected data from the UK Biobank for analysis. MR analysis results revealed a nominal association (p < 0.05) between 17 gut microbial taxa, 31 serum metabolites, and ICH. Among gut microbiota, the higher level of genus Eubacterium xylanophilum (odds ratio (OR): 1.327, 95% confidence interval (CI):1.154-1.526; Bonferroni-corrected p = 7.28 × 10-5) retained a strong causal relationship with a higher risk of ICH after the Bonferroni corrected test. Concurrently, the genus Senegalimassilia (OR: 0.843, 95% CI: 0.778-0.915; Bonferroni-corrected p = 4.10 × 10-5) was associated with lower ICH risk. Moreover, after Bonferroni correction, only two serum metabolites remained out of the initial 31 serum metabolites. One of the serum metabolites, Isovalerate (OR: 7.130, 95% CI: 2.648-19.199; Bonferroni-corrected p = 1.01 × 10-4) showed a very strong causal relationship with a higher risk of ICH, whereas the other metabolite was unidentified and excluded from further analysis. Various sensitivity analyses yielded similar results, with no heterogeneity or directional pleiotropy observed. This two-sample MR study revealed the significant influence of gut microbiota and serum metabolites on the risk of ICH. The specific bacterial taxa and metabolites engaged in ICH development were identified. Further research is required in the future to delve deeper into the mechanisms behind these findings.

The immune factors have complex causal regulation effects on inflammatory bowel disease.

Although a correlation between immune cell phenotypes and inflammatory bowel disease (IBD) has been established, a causal relationship remains unestablished. To assess causal associations between immune cell phenotypes and IBD and its subtypes, we employed Mendelian randomization (MR) methods and genome-wide association studies (GWAS) summary statistics. The primary outcomes were determined based on the inverse variance weighting (IVW) results, with the assessment of heterogeneity and pleiotropy conducted through Cochrane's Q-test and MR-Egger. The stability of the MR results was then examined using leave-one-out analysis, and false discovery rate (FDR) correction was applied to evaluate the strength of the causal relationship between exposure and outcome. Furthermore, to identify immunophenotypes strongly associated with IBD, a meta-integration of the effect values of all positive results in both datasets was conducted. The analysis of 731 immune cell phenotypes and IBD using MR techniques revealed potential causal associations between 26 phenotypes and IBD. Subsequent meta-integration of the two datasets provided evidence of solid causal associations between 18 immune phenotypes and IBD and its subtypes. Nominal causal associations were also identified in the remaining eight immune phenotypes and IBD and its subtypes. Our study confirms causal solid associations between 18 immune phenotypes and IBD, thus guiding future clinical studies.