Helicobacter pylori colonization and obesity - A Mendelian randomization study

Obesity is associated with substantial morbidity, costs, and decreased life expectancy, and continues to rise worldwide. While etiological understanding is needed for prevention, epidemiological studies indicated that colonization with Helicobacter pylori (H. pylori) may affect body mass index (BMI), but with inconsistent results. Here, we examine the relationship between H. pylori colonization and BMI/obesity. Cross-sectional analyses were performed in two independent population-based cohorts of elderly from the Netherlands and Germany (n = 13,044). Genetic risk scores were conducted based on genetic loci associated with either H. pylori colonization or BMI/obesity. We performed a bi-directional Mendelian randomization. Meta-analysis of cross-sectional data revealed no association between anti-H. pylori IgG titer and BMI, nor of H. pylori positivity and BMI. Anti-H. pylori IgG titer was negatively associated with obesity (OR 0.99972; 95% CI 0.99946-0.99997, p = 0.03) and with obesity classes (Beta -6.91 •10-5; 95% CI -1.38•10-4, -5.49•10-7, p = 0.048), but the magnitude of these effects was limited. Mendelian randomization showed no causal relation between H. pylori genetic risk score and BMI/obesity, nor between BMI or obesity genetic risk scores and H. pylori positivity. This study provides no evidence for a clinically relevant association between H. pylori and BMI/obesity

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10−9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies. Delineation of the genetic architecture of hematological traits in a multi-ethnic dataset allows identification of rare variants with strong effects specific to non-European populations and improved fine mapping of GWAS variants using the trans-ethnic approach

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues