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The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors—such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin—higher alcohol drinking, and lower education attainment with increased EOCRC risk. Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions. • We conducted GWAS and MR analyses to identify the causes of EOCRC. • We identified two novel risk loci specific to EOCRC and confirmed the involvement of several known CRC risk variants in EOCRC. • We also identified new EOCRC risk genes and highlighted the prominent role of pathways such as insulin signaling in EOCRC. • We identified probable causal associations for body size, fasting insulin, alcohol intake, and educational level with EOCRC. [ABSTRACT FROM AUTHOR]

Major depression (MD) is a well-recognized risk factor for delirium. However, observational studies cannot provide direct evidence of causality between MD and delirium. This study explored the genetic causal association between MD and delirium using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS) summary data for MD were obtained from the UK Biobank. GWAS summary data for delirium were obtained from the FinnGen Consortium. Inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were used to perform the MR analysis. In addition, the Cochrane's Q test was used to detect heterogeneity in the MR results. Horizontal pleiotropy was detected using the MR-Egger intercept test and MR pleiotropy residual sum and outliers (MR-PRESSO) test. Leave-one-out analysis was used to investigate the sensitivity of this association. The IVW method showed that MD was an independent risk factor for delirium (P = 0.013). Horizontal pleiotropy was unlikely to bias causality (P > 0.05), and no evidence of heterogeneity was found between the genetic variants (P > 0.05). Finally, a leave-one-out test showed that this association was stable and robust. All participants included in the GWAS were of European ancestry. Due to database limitations, the MR analysis did not conduct stratified analyses for different countries, ethnicities, or age groups. We conducted a two-sample MR analysis and found the evidence of genetic causal association between MD and delirium. • A two-sample MR analysis was conducted to explore the causal effect between MD and delirium. • Inverse-variance weighted, MR Egger, weighted median, simple mode, and weighted mode were used to perform the MR analysis. • Heterogeneity and horizontal pleiotropy in the MR results were detected. • We found the evidence of genetic causal association between MD and delirium. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein(a) (Lp(a)) concentrations are a major independent risk factor for coronary artery disease (CAD) and are mainly determined by variation in LPA. Up to 70% of the LPA coding sequence is located in the hypervariable kringle IV type 2 (KIV-2) region. It is hardly accessible by conventional technologies, but may contain functional variants.Objectives: This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD.Methods: We genotyped 4733G>A in the GCKD (German Chronic Kidney Disease) study (n = 4,673) by allele-specific polymerase chain reaction, performed minigene assays, identified proxy single nucleotide polymorphisms and used them to characterize its effect on CAD by survival analysis in UK Biobank (n = 440,234). Frequencies in ethnic groups were assessed in the 1000 Genomes Project.Results: The 4733G>A variant (38.2% carrier frequency) was found in most isoform sizes. It reduces allelic expression without abolishing protein production, lowers Lp(a) by 13.6 mg/dL (95% CI: 12.5-14.7; P < 0.0001) and is the strongest variance-explaining factor after the smaller isoform. Splicing of minigenes was modified. Compound heterozygosity (4.6% of the population) for 4733G>A and 4925G>A, another KIV-2 splicing mutation, reduces Lp(a) by 31.8 mg/dL and most importantly narrows the interquartile range by 9-fold (from 42.1 to 4.6 mg/dL) when compared to the wild type. In UK Biobank 4733G>A alone and compound heterozygosity with 4925G>A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P < 0.001). Frequencies in ethnicities differ notably.Conclusions: Functional variants in the previously inaccessible LPA KIV-2 region cooperate in determining Lp(a) variance and CAD risk. Even a moderate but lifelong genetic Lp(a) reduction translates to a noticeable CAD risk reduction. [ABSTRACT FROM AUTHOR]