Investigation of common genetic risk factors between thyroid traits and breast cancer.

Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 × 10-4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = -0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00-1.13, p-value = 2.8 × 10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 × 10-2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0 × 10-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 × 10-8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.

Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

BACKGROUND: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. OBJECTIVE: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. METHODS: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. RESULTS: We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). CONCLUSIONS: We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited.

BACKGROUND: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. OBJECTIVE: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. METHODS: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. RESULTS: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, PInteraction  = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. CONCLUSIONS: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study.

BACKGROUND: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. OBJECTIVE: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). METHODS: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). RESULTS: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029). CONCLUSIONS: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.

Leveraging pleiotropic association using sparse group variable selection in genomics data.

BACKGROUND: Genome-wide association studies (GWAS) have identified genetic variants associated with multiple complex diseases. We can leverage this phenomenon, known as pleiotropy, to integrate multiple data sources in a joint analysis. Often integrating additional information such as gene pathway knowledge can improve statistical efficiency and biological interpretation. In this article, we propose statistical methods which incorporate both gene pathway and pleiotropy knowledge to increase statistical power and identify important risk variants affecting multiple traits. METHODS: We propose novel feature selection methods for the group variable selection in multi-task regression problem. We develop penalised likelihood methods exploiting different penalties to induce structured sparsity at a gene (or pathway) and SNP level across all studies. We implement an alternating direction method of multipliers (ADMM) algorithm for our penalised regression methods. The performance of our approaches are compared to a subset based meta analysis approach on simulated data sets. A bootstrap sampling strategy is provided to explore the stability of the penalised methods. RESULTS: Our methods are applied to identify potential pleiotropy in an application considering the joint analysis of thyroid and breast cancers. The methods were able to detect eleven potential pleiotropic SNPs and six pathways. A simulation study found that our method was able to detect more true signals than a popular competing method while retaining a similar false discovery rate. CONCLUSION: We developed feature selection methods for jointly analysing multiple logistic regression tasks where prior grouping knowledge is available. Our method performed well on both simulation studies and when applied to a real data analysis of multiple cancers.

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.

Replication of a Novel Parkinson's Locus in a European Ancestry Population.

BACKGROUND: A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17. OBJECTIVES: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations. METHODS: We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled. RESULTS: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean  = 6.64 × 10-4 , pooled PD P = 1.15 × 10-11 ). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10-8 ). CONCLUSIONS: Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Bayesian meta-analysis models for cross cancer genomic investigation of pleiotropic effects using group structure.

An increasing number of genome-wide association studies (GWAS) summary statistics is made available to the scientific community. Exploiting these results from multiple phenotypes would permit identification of novel pleiotropic associations. In addition, incorporating prior biological information in GWAS such as group structure information (gene or pathway) has shown some success in classical GWAS approaches. However, this has not been widely explored in the context of pleiotropy. We propose a Bayesian meta-analysis approach (termed GCPBayes) that uses summary-level GWAS data across multiple phenotypes to detect pleiotropy at both group-level (gene or pathway) and within group (eg, at the SNP level). We consider both continuous and Dirac spike and slab priors for group selection. We also use a Bayesian sparse group selection approach with hierarchical spike and slab priors that enables us to select important variables both at the group level and within group. GCPBayes uses a Bayesian statistical framework based on Markov chain Monte Carlo (MCMC) Gibbs sampling. It can be applied to multiple types of phenotypes for studies with overlapping or nonoverlapping subjects, and takes into account heterogeneity in the effect size and allows for the opposite direction of the genetic effects across traits. Simulations show that the proposed methods outperform benchmark approaches such as ASSET and CPBayes in the ability to retrieve pleiotropic associations at both SNP and gene-levels. To illustrate the GCPBayes method, we investigate the shared genetic effects between thyroid cancer and breast cancer in candidate pathways.

Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood.

BACKGROUND: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. OBJECTIVE: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood. METHODS: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totalling 8273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analysed. RESULTS: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P = 4.3 × 10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P < 5 × 10-6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P = 4.9 × 10-7 ), 14q22 (rs7493885 near NIN; P = 2.9 × 10-6 ) and 2p22 (rs232542 near CYP1B1; P = 4.1 × 10-6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings. CONCLUSIONS AND CLINICAL RELEVANCE: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms.