GWAS summary statistics from Casanova <i>et al. </i>2024 "Iron and risk of dementia: Mendelian randomization analysis in UK Biobank"

GWAS summary statistics from the published paper: Iron and risk of dementia: Mendelian randomization analysis in UK Biobank Casanova et al. (2024) Journal of Medical Genetics. doi: jmg-2023-109295 AbstractBackground: Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter. Methods: We analyzedanalysed UK Biobank participants clustered into European (N=4 51 284), African (N=7477), and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project. Using Mendelian randomizsation methods, we estimated the association between genetically predicted serum iron (transferrin saturation [(TSAT]) and ferritin), grey matter volume, and genetic liability to clinically defined dementia (including Alzheimer’s disease [(AD]), non-AD, and vascular dementia) from hospital and primary care records. We also performed time-to-event (competing risks) analysis of the TSAT polygenic score on risk of clinically defined non-AD dementia. Results: In Europeans, higher genetically predicted TSAT increased genetic liability to dementia (Odds RatioOR: 1.15, 95% Confidence IntervalsI 1.04– to 1.26, pp=0.0051), non-AD dementia (OR: 1.27, 95% CI 1.12 to 1.45, pp=0.00018), and vascular dementia (OR:1.37, 95% CI 1.12 to 1.69, pp=0.0023), but not AD (OR: 1.00, 95% CI 0.86 to 1.15, pp=0.97). Higher TSAT was also associated with increased risk of non-AD dementia in participants of African, but not South Asian groups. In survival analysis using a TSAT polygenic score, the effect was independent of Aapolipoprotein-E ε4 genotype (with adjustment sub-distribution Hazard RatioR: 1.74, 95% CI 1.33 to 2.28, pp=0.00006). Genetically predicted TSAT was associated with lower grey matter volume in caudate, putamen and thalamus, and not in other areas of interest. Discussion: Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-Alzheimer’sD and vascular dementia, in European and African groups. This association appears to be independent of APOE eapolipoprotein-E ε4. Methods for GWAS in UK BiobankGenetic associations with dementia were tested using “SAIGE” (Scalable and Accurate Implementation of Generalized mixed model) v0.35, which controls for unbalanced case-control ratios and for sample relatedness using mixed-model approaches. Genetic associations for quantitative traits (i.e., inverse-normalized MRI phenotypes) were tested using “BOLT-LMM” v2.3.2, which performs linear mixed-effects models to efficiently control for sample relatedness. UK Biobank imputed genotypes (v3 data release, n=93 million) were analyzed. GWAS were adjusted for age, sex, study center (1-22), and genotyping microarray (2) at run time. Variants with imputation quality (INFO) <0.3, minor allele frequency (MAF) <0.1%, or significant deviation from Hardy-Weinberg Equilibrium (HWE p<5*10-8) were excluded, leaving ~16million for subsequent analysis. GWAS summary statistics file names:Two tar archives are included. The "dementia" GWAS (dementia, dementia_ad, dementia_notad, and dementia_vasc). For each outcome, there are also sex-stratified results with the suffix _m or _f.The "MRI grey matter" GWAS, based on data from up to 46,000 participants. Files are prefixed "mri46_gm", with the specific region then named (e.g., caudate, ifg, etc.). Below are the names of all 17 phenotypes tested, grouped by region:Frontal :: Inferior frontal gyrusFrontal :: Middle frontal gyrusFrontal :: Precentral gyrusFrontal :: Superior frontal gyrusFrontal :: Supplementary motor cortexParietal :: PrecuneusParietal :: Postcentral gyrusParietal :: Superior parietal lobeSubcortical :: AmygdalaSubcortical :: CaudateSubcortical :: HippocampusSubcortical :: PallidumSubcortical :: PutamenSubcortical :: ThalamusTemporal :: Interior temporal gyrusTemporal :: Middle temporal gyrusTemporal :: Parahippocampal gyrusGWAS summary statistics file headers:variant_id [rsID where available, otherwise chr:bp_OA_EA] chromosome base_pair_location [GRCh37] effect_allele other_allele effect_allele_frequency beta standard_error p_value [for BOLT-LMM, this is the P_BOLT_LMM column]