Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study

BACKGROUND: Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. METHODS AND FINDINGS: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 microg/dl increase in serum iron. CONCLUSIONS: Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be mad

Pain sensitivity is modulated by affective temperament: Results from the population-based CHRIS Affective Disorder (CHRIS-AD) study

Background: Nociceptive pain modulation is related to psychological and psychiatric conditions. Evidence from clinical studies backs innate temperaments as potential precursors of mood symptoms and disorders, and pain sensitivity. Our study examines the modulation effect of affective temperaments on pain sensitivity in a general population adult sample, accounting for possible intervening mood symptoms, lifetime anxiety and depression, and pain treatments.Methods: The sample is part of the CHRIS-AD study, Italy. Primary outcomes were the pain sensitivity ques-tionnaire PSQ-total intensity score and the experimental pressure pain threshold (PPT). Affective temperaments were evaluated with the TEMPS-M. Lifetime depression, anxiety, current mood disorders, and treatments were self-reported via rating-scales. Directed acyclic graphs theory guided linear and mixed linear regression model analyses.Results: Among 3804 participants (aged 18-65; response rate 78.4 %, females 53.3 %, mean age 38.4 years) for any given temperament, both the PSQ-total and the PPT were associated with temperament. The TEMPS-M four cyclothymic-related temperaments aligned on the pain-sensitive pole and the hyperthymic on the pain-resilient pole. The inclusion of current or lifetime mood symptoms, or pain drug use, as possible intervening pathways only partly diluted these associations, with stronger evidence for an effect of trait anxiety. Limitations: The main limitations were the lack of experimental measures of suprathreshold pain intensity perception, and detailed information on affective disorders in the study population. Conclusions: These findings support the hypothesis of a biological dichotomous diathesis of affective temperaments towards pain sensitivity; hyperthymic suggesting protection, whereas cyclothymic suggesting predisposition

Development and evaluation of a kidney health questionnaire and estimates of chronic kidney disease prevalence in the Cooperative Health Research in South Tyrol (CHRIS) study

Background: Kidney diseases are a public health burden but are poorly investigated in the general population. In light of inadequate survey tools, we developed a novel questionnaire for use in population-based studies, to retrospectively assess kidney diseases. Methods: The questionnaire covered general kidney diseases, reduced kidney function, and renal surgeries. It was administered between 2011 and 2018 to 11,684 participants (median age = 45 years) of the Cooperative Health Research in South Tyrol (CHRIS) study. Fasting estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were measured. By factor analysis we contextualized the questionnaire content with respect to the biochemical measurements. We estimated overall and sex-stratified prevalence of kidney diseases, including possible CKD, calibrating them to the general target population via relative sampling weights. Results: Population-representative prevalence of glomerulonephritis, pyelonephritis, and congenital kidney diseases was 1.0%, 3.0%, and 0.2%, respectively, with corresponding odds ratios for females versus males of 1.4 (95% confidence interval: 1.0, 2.0), 8.7 (6.2, 12.3), and 0.7 (0.3, 1.6), respectively. Prevalence of kidney dysfunction (eGFR < 60 mL/min/1.73 m2 or UACR > 30 mg/g) was 8.59%, while prevalence of self-reported CKD was 0.69%, indicating 95.3% of lack of disease awareness, with a similar figure in people with diabetes or hypertension. Overall, 15.76% of the population was affected by a kidney disease of any kind. Conclusion: In the Val Venosta/Vinschgau alpine district, CKD prevalence aligned with Western European estimates. Kidney health questionnaire implementation in population studies is feasible and valuable to assess CKD awareness, which we found to be dramatically low

Associations between dietary patterns and kidney health assessed in the population-based CHRIS study using reduced rank regression

Objective: While diet plays a key role in CKD management, the potential for diet to impact CKD prevention in the general population is less clear. Using a priori knowledge, we derived disease-related dietary patterns (DPs) through reduced rank regression (RRR) and investigated associations with kidney function, separately focusing on generally healthy individuals and those with self-reported kidney diseases, hypertension or diabetes mellitus. Methods: 8,686 participants from the population-based Cooperative Health Research in South Tyrol (CHRIS) study were split into a group free of kidney disease, hypertension and diabetes (n=6,133) and a group with any of the three conditions (n=2,553). Diet was assessed through the self-administered GA2LEN food frequency questionnaire (FFQ) and DPs were derived through RRR selecting FFQ-derived sodium, potassium, phosphorus and protein intake as mediators. Outcomes were creatinine-based estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), CKD and microalbuminuria. Multiple linear and logistic models were used to assess associations between RRR-based DPs and kidney outcomes separately in the two analytic groups. Results: We identified three DPs, where high adherence reflected high levels of all nutrients (DP1), high potassium-phosphorus and low protein-sodium levels (DP2), and low potassium-sodium and high protein-phosphorus levels (DP3), respectively. We observed heterogeneous associations with kidney outcomes, varying by analytic group and sex. Kidney outcomes were much more strongly associated with DPs than with single nutrients. Conclusion: RRR is a feasible approach to estimate disease-related DPs and explore the combined effects of nutrients on kidney health. Heterogeneous associations across kidney outcomes suggest possible specificity to kidney function or damage. In individuals reporting kidney disease, hypertension or diabetes, specific dietary habits were associated with better kidney health, indicating that disease-specific dietary interventions can be effective for disease control

Genome-Wide Association Study Identifies Multiple Genetic Loci for Activated Partial Thromboplastin Time and Prothrombin Time

Abstract Abstract 4222 Background: Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are commonly used to screen for coagulation factor deficiencies. Shorter aPTT is also a risk marker for incident and recurrent venous thromboembolism (VTE). Genetic factors influencing aPTT and PT are not well understood. So far only one genome-wide association study (GWAS) has been reported for aPTT in 1,477 participants and none for PT. Methods: We conducted a GWAS for the aPTT in 9,240 European Americans (EAs) from the Atherosclerosis Risk in Communities (ARIC) study and for PT in 1,221 EAs from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS). Replication was assessed by in silico analysis in MICROS (aPTT, n=1,215) and the Lothian Birth Cohorts (LBC) (LBC1936 (aPTT and PT, n=925-989), LBC1921 (aPTT, n=445)), and by de novo genotyping in the Caerphilly study (aPTT, n=882). Subjects on anticoagulants were excluded. Genotyping was conducted with the Affymetrix single nucleotide polymorphism (SNP) array 6.0 or Illumina HumanHap300/370 and imputed to ∼2.5 million HapMap SNPs. SNPs with imputation quality score &lt; 0.3 or minor allele frequencies ≤1% were excluded from data analysis. The imputed SNP dosages were analyzed in linear regression adjusted for age, sex, and field center, where applicable. Results: Five loci were associated with aPTT at genome-wide significance of p&lt;5×10-8 that have not been previously reported: F5 (1q23, top SNP rs9332701, missense, β (effect size associated with one copy increase in minor allele)=0.54, p=3.7×10-8), F11 (4q35, rs1593, intronic, β =0.54 and 0.36, p=1.25×10-17 and 2.0×10-8 before and after adjusting for known variants in F11), NSD1 (5q35.2-q35.3, rs11950938, intronic, β =1.00 and 1.21, p=1.11×10-15 and 1.5×10-22 before and after adjusting for known variants in F12 of the same region), C6orf10 (6p21.3, rs2050190, intronic, β =-0.25, p=1.3×10-8), and ABO (9q34.1-q34.2, rs8176704, intronic, tag for A2 group, β =0.19 and 0.89, p=0.02 and 4.3×10-24 before and after adjusting for O blood group). Three of the five loci replicated in at least one replication sample and the other two were directionally consistent in 3 replication samples. Furthermore, meta-analysis pooling the discovery and replication GWAS samples yielded two additional independent loci at chromosomes 1q23 (F5, best SNP rs6028, coding-synonymous, β =0.23, p=5.97×10-9) and 15q25.3 (AGBL1, rs2469184, intronic, β =0.16, p= 4.24×10-8), with consistent associations across studies. The signals at the F5 region were not due to FV Leiden (rs6025, p=0.46 in ARIC). We also confirmed previously reported loci in KNG1, HRG, F11, F12, and ABO (O group). For PT, novel associations from two gene regions reached genome-wide significance in MICROS: F7 (top SNP rs3093253, within an exon but not translated, β =-5.44, p=8.2×10-19) and PROCR (rs6060244, near PROCR, β =4.11, p=3.5×10-9). Both loci replicated in LBC1936. Conclusions: In this large GWAS, six of the nine novel loci associated with the aPTT and PT are coagulation-related and the other three (NSD1, C6orf10, and AGBL1) are new candidate genes not directly involved in coagulation. The C6orf10 gene interacts with TNF-a at the transcription level and was previously associated with inflammatory diseases. These findings may be relevant to the prevention and treatment of coagulation disorders including VTE. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Evidence of Inbreeding Depression on Human Height

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance

A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site

AbstractWe recently identified 68 genomic loci where common sequence variants are associated with platelet count and volume. Platelets are formed in the bone marrow by megakaryocytes, which are derived from hematopoietic stem cells by a process mainly controlled by transcription factors. The homeobox transcription factor MEIS1 is uniquely transcribed in megakaryocytes and not in the other lineage-committed blood cells. By ChIP-seq, we show that 5 of the 68 loci pinpoint a MEIS1 binding event within a group of 252 MK-overexpressed genes. In one such locus in DNM3, regulating platelet volume, the MEIS1 binding site falls within a region acting as an alternative promoter that is solely used in megakaryocytes, where allelic variation dictates different levels of a shorter transcript. The importance of dynamin activity to the latter stages of thrombopoiesis was confirmed by the observation that the inhibitor Dynasore reduced murine proplatelet for-mation in vitro.</jats:p

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research