Kidney stone disease GWAS meta-analysis- FinnGen & UK Biobank

A fixed-effects meta-analysis of kidney stone disease was undertaken using UK Biobank and FinnGen kidney stone GWAS summary statistics for autosomes and the X-chromosome. FinnGen r8 GWAS data are publicly available for the phenotype N14 calculus of kidney and ureter comprising 8597 cases and 333,128 controls. Information on sample phenotyping, genotyping, and GWAS in the FinnGen sample has been previously described. SNPs with MAF 75%) were excluded. The resultant summary statistics were used to perform MR analyses.</p

Summary statistics for kidney stone GWAS in UK Biobank

Genome-wide association studies (GWAS) were performed in the UK Biobank, excluding participants with conditions predisposing to kidney stone disease (Supplementary Table 3). Genotyping was undertaken using UK-BiLEVE and UK-Biobank Axiom Arrays and called using array intensity data and a custom genotype-calling pipeline. PLINKv1.9 and Rv3.6.1 were used for quality control (QC). Sample-, individual-, and SNP-level QC exclusions are shown in Supplementary Methods.UK Biobank phasing on autosomes was performed with SHAPEIT3 using the 1000 Genomes phase 3 dataset as a reference panel. The Haplotype Reference Consortium reference panel and a merged UK10K/1000 Genomes Phase 3 panel were used in imputation. The resultant dataset comprised 92,693,895 autosomal SNPs, short indels, and large structural variants.A total of 547,011 genotyped and 8,397,548 imputed autosomal SNPs and 733,758 genotyped and 2,635,881 X-chromosome SNPs with MAF ≥0.01 and Info Score ≥0.9 were used at GWAS, using a linear mixed noninfinitesimal model implemented in BOLT-LMMv2.3</p

Association of genetic score using synthesis SNPs for 25(OH)D concentration with risk of diabetes in a meta-analysis of all studies per 25-nmol/l higher genetically instrumented 25(OH)D concentration.

<p>Values shown are the odds ratios (95% CIs) per 25-nmol/l higher 25(OH)D concentration among studies stratified by latitude into northern (>50°) or southern latitude (≤50°). The area of the squares is proportional to the inverse variance of each effect size. *The effects of all SNPs on risk of diabetes in Chinese and European populations were weighted by their effects on 25(OH)D concentration. 25(OH)D, 25-hydroxyvitamin D; CCCS, Cambridgeshire case—control study; CKB, China Kadoorie Biobank; DIAGRAM, Diabetes Genetics Replication and Meta-analysis; UKB, UK Biobank.</p

Association of 25(OH)D SNPs with plasma 25(OH)D concentrations and with cardiometabolic risk factors.

<p>Association of 25(OH)D SNPs with plasma 25(OH)D concentrations and with cardiometabolic risk factors.</p

Selected characteristics for all participants with 25-hydroxyvitamin D (25[OH]D) measured and genetic data in the China Kadoorie Biobank (CKB).

<p>Selected characteristics for all participants with 25-hydroxyvitamin D (25[OH]D) measured and genetic data in the China Kadoorie Biobank (CKB).</p

Data_Sheet_1.docx

<p>Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ∼5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 × 10^-35), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the“COPI-mediated anterograde transport” gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.</p

Clinical characteristics of the study groups.

<p>Clinical characteristics of the study groups.</p

Functional consequences of variants in the <i>SERPINA6/A1</i> locus significantly associated with morning plasma cortisol in GWAMA, and of the Leuven variant, in CROATIA-Korcula.

a<p>Data for total cortisol is from the whole Croatia-Korcula sample, n = 898.</p>b<p>Samples selected for measured free cortisol assay were age and sex matched homozygotes at rs12589136.</p>c<p>adjusted for age, sex, and first three principal components, using kinship matrix derived from GWAS data.</p><p>Data are geometric mean (95% CI)[n]. Cortisol values are nmol/L, CBG µmol/L, cortisol binding activity nmol/L, and α1-antitrypsin g/L. RCL = reactive centre loop.</p