INTRODUCTION:Modifiers of the association between hormone replacement therapy (HRT) use and dementia risk and responsive subgroups, are unknown. METHODS:In 183,450 postmenopausal women from the UK Biobank (mean 13.3 years follow-up), multivariable Cox regression models evaluated associations between HRT use (≥1 year) and all-cause dementia and dementia subtypes. Stratified analyzes assessed modification by menopause type, lifetime estrogen exposure, apolipoprotein E (APOE) ɛ4 genotype, and age at HRT initiation. RESULTS:Over 2.43 million person-years, 3,948 dementia cases were identified. HRT use was associated with lower all-cause dementia (hazard ratio [HR] 0.90; 95% CI, 0.84-0.96), with stronger associations in surgical menopause (0.74, 0.65-0.84), APOE ɛ4 carriers (0.87, 0.80-0.95) and women with lower endogenous estrogen exposure (0.84, 0.77-0.93). Initiation between ages 46 and 56 conferred the greatest benefit. DISCUSSION:HRT use was associated with lower dementia risk, and these findings may help inform more tailored approaches to HRT prescribing in relation to women's lifetime dementia risk.

Abstract Purpose Haemochromatosis due to HFE -C282Y homozygosity can lead to excess iron absorption and is typically associated with liver malignancy, plus widespread arthritis. Recent evidence suggests that limb fractures are more common, but little is known about vertebral effects. This study investigated the association of vertebral compression fractures, assessed with intelligent dual-energy X-ray absorptiometry (iDXA), and HFE genotype in a large community cohort. Methods UK Biobank data from 227 European genetic ancestry C282Y homozygotes (mean 64.6 years) and 234 age, sex, and BMI-matched controls without common HFE haemochromatosis variants were included. Lateral vertebral assessment scans (iDXA, GE-Lunar) were acquired at imaging reassessment (2014-2020) and reviewed, blind to genotype, for radiological evidence of vertebral fracture. Matched logistic regression models assessed associations between C282Y homozygosity and vertebral fractures. Results 78 vertebral fractures (16.9%) were identified within 461 participants. Male C282Y homozygotes had increased odds of vertebral fracture (n=22/89, 24.7%) compared to participants without HFE alleles (n=9/90, 10.0%); Odds Ratio [OR]: 2.95, 95%CI: 1.28–6.85, p=0.01. The association persisted after excluding individuals with a diagnosis of haemochromatosis (OR: 3.37, 95% CI: 1.41–8.10, p=0.007). No excess fracture risk was observed in female C282Y homozygotes (n=23/138, 16.7%) vs those without HFE alleles (n=24/144, 16.7%); OR: 0.99, 95%CI: 0.53-1.87, p=1.00. Conclusion In this community-based imaging study, male HFE C282Y homozygotes had a markedly higher likelihood of vertebral fractures than those without HFE variants. These findings support further evaluation of vertebral fracture assessment in C282Y homozygous men to ensure prompt treatment to prevent future fracture if appropriate.

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15's mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation. Exposure of cultured myeloid cells to recombinant GDF15 altered biological pathways that we subsequently demonstrated are predictive of dementia risk, including interferon/antiviral responses. These findings support circulating GDF15's role as an early biomarker-particularly for vascular dementia and neuroinflammation-and identify the mechanisms by which it may drive dementia risk.

Medication adherence is essential to ensure treatment effectiveness, but too often in routine care non-adherence compromises the desired outcome. We explore longitudinal causal modelling using observational data to estimate the time-varying effects of continuous drug adherence measures on health outcomes over a sustained period. The goal of such analyses is to quantify the potential impact of interventions to improve adherence on long-term health. We consider two established longitudinal causal approaches designed to handle time-varying confounding under the “no unmeasured confounding” (NUC) assumption: G-estimation and inverse probability of treatment weighting (IPTW). In randomized controlled trial, NUC-based methods have been applied to address non-adherence as an intercurrent event, and instrumental variable (IV) extensions of G-estimation have also been introduced for settings where the NUC assumption may fail. We adapt these methods to observational data settings and illustrate their use for assessing how adherence over time impacts health outcomes. We align the causal parameters across methods and show they can target the same causal estimand: the average effect among treated individuals of full adherence versus zero adherence. We set out the identification conditions for IPTW and G-estimation under NUC, and for an IV-based extension that has specific utility when the NUC assumption is implausible. We assess the statistical properties, strengths and weaknesses of each approach through Monte Carlo simulations designed to reflect longitudinal studies with a continuous exposure. We demonstrate these methods by quantifying the effect of full statin adherence on LDL cholesterol control in 13,000 UK Biobank participants with linked primary care data.

We previously identified genetic correlation between pairs of musculoskeletal (MSK) and respiratory conditions. Strategies to prevent or delay their onset remain underexplored in the context of multimorbidity. This study investigated whether MSK–respiratory disease pairs show evidence of potential causal relationships, identified modifiable risk factors, and quantified intervention windows to prevent progression to multimorbidity. We examined combinations of one respiratory condition (asthma, COPD) and one MSK condition [rheumatoid arthritis (RA), osteoarthritis (OA), polymyalgia rheumatica (PMR), psoriasis]. Two-sample Mendelian randomisation (MR) evaluated potential causal relationships in both directions. Linked electronic health records from CPRD (N = 11,042,985; age ≥ 40 years) were used to assess longitudinal disease trajectories, prognostic consequences, and mediation by potentially modifiable or treatable factors. We found evidence for bidirectional relationships between COPD and RA/OA (ORs 1.10–1.19) and between asthma and RA/OA (ORs 1.03–1.14). COPD genetic liability also increased PMR risk (OR 1.14, 95

BACKGROUND & AIMS:The iron overload disease haemochromatosis is primarily caused by HFE p.C282Y homozygosity, yet penetrance of clinical outcomes (including liver disease/cancer) varies. We aimed to estimate the effect of genetic and lifestyle factors on disease penetrance and expressivity in HFE C282Y homozygotes. METHODS:We analysed 2,893 C282Y homozygous UK Biobank participants (n = 1,295 male). We ascertained haemochromatosis from medical records, liver disease/cancer, osteoarthritis, joint replacement surgeries, and dementia diagnoses. We derived polygenic scores (PGS) for iron biomarkers, including hepcidin and transferrin saturation (TSAT). Sex-stratified logistic regression assessed associations with clinical outcomes. We used time-to-event regression estimating effects of age, lifestyle, and PGS, and estimated effects of rare HFE variants using whole-genome sequencing data. RESULTS:In male HFE C282Y homozygotes, higher TSAT PGS increased the likelihood of diagnosis of haemochromatosis, and separately any clinical consequence (odds ratio [OR]top-vs-bottom-PGS-quintile = 1.83, 95% CI: 1.26-2.66, p = 0.001). Cumulative incidence of assessed haemochromatosis clinical outcomes in men by age 80 years was 64.5% (highest quintile) vs. 51.6% (lowest) (p for difference = 0.025). In women, TSAT PGS increased haemochromatosis likelihood (cumulative incidence: 45.3% vs. 23.3% [highest/lower quintile], p = 0.00001) but not liver disease. PGS for other iron biomarkers was not significantly associated with clinical outcomes. Rare heterozygous predicted loss-of-function variants in HFE increased haemochromatosis likelihood in non-C282Y homozygotes (aggregate OR = 14.8, 95% CI 4.7-41.1, p = 0.003), highlighting the importance of sequencing undiagnosed individuals to find rare causes of haemochromatosis. CONCLUSION:Higher genetically predicted TSAT significantly increased risk of clinical outcomes in HFE C282Y homozygotes. Combined with modifiable lifestyle factors, genetic information could refine risk stratification and personalise iron monitoring, following validation. IMPACT AND IMPLICATIONS:There is a pressing clinical need to understand the wide variation in clinical outcomes observed in HFE C282Y homozygotes. Higher genetically predicted TSAT significantly increased the risk of clinical outcomes, including liver and musculoskeletal complications, in HFE C282Y homozygotes, highlighting non-HFE genetic influence on disease penetrance. These results are relevant for physicians and researchers, because combining genetic factors (TSAT PGS) with demographic and lifestyle factors provided the highest prediction accuracy for haemochromatosis and related clinical outcomes. Practically, integrating polygenic risk assessments with existing patient care pathways could enhance precision therapies by enabling the earlier, targeted management of high-risk HFE C282Y homozygotes, although external validation of these predictive models is required before clinical adoption.

BACKGROUND:Multimorbidity, the co-occurrence of multiple long-term conditions (LTCs), is an increasingly important clinical problem, but little is known about the underlying causes. We investigate the role of a critical multimorbidity risk factor, obesity, as measured by body mass index (BMI), in explaining shared genetics amongst 71 common LTCs. METHODS:In a population of northern Europeans, we estimated genetic correlation, between LTCs and partial genetic correlations after adjustment for the genetics of BMI. We used multiple causal inference methods to confirm that BMI causally affects individual LTCs, and their co-occurrence. Finally, we quantified the population-level impact of intervening and lowering BMI on the prevalence of 15 key common multimorbid LTC pairs. RESULTS:BMI partially explains some of the shared genetics for 740 LTC pairs (30% of all pairs considered). For a further 161 LTC pairs, the genetic similarity between the LTCs was entirely accounted for by BMI genetics. This list included diabetes and osteoarthritis and gout and osteoarthritis: Causal inference methods confirmed that higher BMI acts as a common risk factor for a subset of these pairs, and therefore BMI-lowering interventions would likely reduce their prevalence. For example, we estimated that a 1 standard deviation or 4.5 unit decrease in BMI would result in 17 fewer people with both chronic kidney disease and osteoarthritis per 1000 who currently have both LTCs. CONCLUSIONS:Our genetics-centred approach quantifies the contribution of obesity to multi-morbidity. Our method for calculating full and partial genetic correlations is published as an R package {partialLDSC}.

INTRODUCTION:HFE genetic variants, especially C282Y homozygosity (C282Y+/+), can increase systemic iron and cause hemochromatosis, though expression varies. Excess iron can lead to liver disease and liver cancer, yet factors influencing liver iron beyond HFE genotype remain unclear. We investigated genetic/environmental factors influencing liver iron, including HFE genotype and hemochromatosis diagnosis. METHODS:We analyzed 37,287 European ancestry UK Biobank participants (mean age 64.1, SD: 7.6) with HFE genotypes and MRI-estimated liver iron concentrations (MRLIC). Linear regression assessed MRLIC associations with genetic and environmental factors, adjusting for age, sex, and genetic covariates. RESULTS:Mean MRLIC was highest in undiagnosed C282Y+/+ males and females (2.56 and 2.31 mg/g) versus diagnosed (1.23 and 1.51 mg/g, p=0.0001 and 0.0004). Other HFE genotypes had nominal increases versus those without HFE genetic variants. Higher MRLIC was associated with higher alcohol intake (β=0.11, 95% CI: 0.09-0.11, p=6.0×10-128; >30 vs. 1-14 units/wk), frequent red/processed meat consumption (β=0.08, 95% CI: 0.07-0.09, p=3.7×10-54; ≥3 times/week vs. none), high waist-height ratio (β=0.01, 95% CI: 0.006-0.02, p=6.4×10-5; although magnitude was weak) and genetically predicted transferrin saturation (β=0.22, 95% CI: 0.19-0.26, p=3.8×10-46). Lower MRLIC was associated with underweight body mass index (β=-0.06, 95% CI: -0.09 to -0.03, p=1.1×10-4) and proton pump inhibitor use (β=-0.03, 95% CI: -0.04 to -0.03, p=3.5×10-17). CONCLUSIONS:Undiagnosed C282Y+/+ individuals had excess liver iron versus diagnosed, likely due to treatment. Genetic and environmental factors influence liver iron beyond C282Y+/+. Tailored lifestyle advice could benefit those at risk of hemochromatosis.

The mitochondrial cascade hypothesis suggests that mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer’s disease dementia. Recent data have shown that mitochondrial DNA copy number (mtDNAcn) in human blood is associated with dementia risk and cognitive function, but which specific cognitive measures or domains are associated with mitochondrial dysfunction and whether this relationship is affected by health deterioration such as physical frailty or mitochondrial somatic mutations is not clear. We measured mtDNAcn and heteroplasmies using fastMitoCalc and MitoCaller, respectively, from UK Biobank Whole Genome Sequencing (WGS) data at study entry (2006-2010). Pre-frail/frail status was determined by the presence of slow gait, weight loss, low grip strength, exhaustion, or low physical activity. Cognitive function was assessed in a subset of participants (mean age=64.1,51.7% women, 97.0% White) on average 8.9 years after study entry, including processing speed via Digit Symbol Substitution Test (DSST)(n=13,940), attention via Trail Making Test (TMT) part A(n=13,482), executive function via delta TMT(n=13,428) and tower rearranging task(n=13,819), memory via paired associative learning task(n=14,094), and fluid reasoning via matrix pattern completion task(n=13,935). We examined the associations between mtDNAcn and cognitive measures using multivariate linear regression, adjusted for demographic factors, smoking status, follow-up time, measures related to mtDNAcn assessment, and Apolipoprotein E ε4 status. We then stratified the analysis by frailty status and levels of heteroplasmy load. Overall, more mtDNAcn was significantly associated with higher DSST (p=0.036) but not with other cognitive measures. After stratification by frailty status, mtDNAcn was associated with DSST, delta TMT, and paired associative learning in the pre-frail/frail participants only (p=0.047,0.007, and 0.044, respectively). After stratification by a median split of heteroplasmy load, mtDNAcn was associated with DSST and paired associative learning in those with higher heteroplasmy load (p=0.039 and 0.031, respectively). Results remained similar after excluding participants with dementia diagnosis (n=15). Higher mitochondrial DNA copy number from human blood is associated with higher cognition in specific measures. The associations with processing speed, executive function, and memory are prominent in individuals with health deterioration of physical frailty or high level of mtDNA heteroplasmy. Future studies are warranted to understand the biological underpinnings.

Importance: The relationship between HRT use and dementia risk is unclear, with studies reporting both increased and decreased risk. Objective: To identify modulators of the association between HRT use and dementia risk and identify potentially responsive subgroups of women. Design, setting, and participants: This study used data from the UK Biobank, with baseline assessment conducted between 2006 and 2010 and follow up through to October 2022. The cohort included post-menopausal women without a diagnosis of dementia at baseline. Exposures: The primary exposure was HRT use for a minimum duration of one year. Main outcomes and measures: Multivariable Cox proportional hazards regression models were employed to evaluate the relationship between HRT use and incident all-cause dementia, Alzheimer's disease (AD) and non-AD dementia. Stratified analyses were conducted to explore heterogeneity in the associations and the impact of potential effect modifiers, including type of menopause (surgical vs. natural), cumulative lifetime exposure to natural estrogen and APOE ɛ4 genotype. The association between age at HRT initiation and dementia risk was also examined. Results: Among 183,450 postmenopausal women (mean [SD] age at baseline, 60.3 [5.8] years), there were 3,948 dementia cases over 2,433,320 person-years of follow-up. Of these, 1,993 (50.5%) were classified as AD and 1,955 (49.5%) as non-AD dementia. HRT use was associated with lower risk of all-cause dementia (hazard ratio [HR], 0.90; 95% CI, 0.84-0.96). Stronger associations were observed in women with surgical menopause (HR 0.76; 95% CI, 0.67-0.85), APOE ɛ4 carriers (HR 0.87; 95% CI, 0.80-0.95 ), and those with a lower lifetime exposure to natural estrogen (HR 0.78; 95% CI, 0.70-0.86). Initiation of HRT between 46 and 56 years was associated with reduced dementia risk . Conclusions and relevance: In this large UK Biobank cohort, HRT use was associated with reduced risk of dementia among post-menopausal women. The association varied by age of initiation of HRT, APOE genotype, type of menopause, and endogenous lifetime estrogen exposure, highlighting the importance of personalised approaches to HRT prescribing. While further research is required to establish causality, the findings offer a foundation for tailored interventions aimed at mitigating lifetime dementia risk in women. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by a UK Biotechnology and Biological Sciences Research Council (BBSRC/UKRI) project grant, BB/X002209/1. JLA is funded by an NIHR Advanced Fellowship (NIHR301844). JR is funded by Alzheimer's Research UK. Alzheimer's Research UK (DJL), the National Institute for Health and Care Research (NIHR) Applied Research Collaboration South West Peninsula (DJL), and the NIHR Exeter Biomedical Research Centre (DJL). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study used only UK Biobank data which is available to researchers through application to: https://www.ukbiobank.ac.uk/. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes UK Biobank data is available to researchers through application to: https://www.ukbiobank.ac.uk/.

Growth/differentiation factor-15 (GDF15) has been associated with dementia risk, yet its predictive value across cohorts and sub-population, as well as its relationship with endophenotypes relevant to dementia, remains unknown. Using the Atherosclerosis Risk in Communities (ARIC) study as the discovery cohort, we examined the relationship between plasma GDF15 levels (SomaScan) and risk for incident all-cause dementia (ACD) in late-life (N=4,287, 7-year follow-up, M age =75±5) and in midlife (N=11,595, 20-year follow-up, M age =57±6). Utilizing the UK Biobank (UKB; replication cohort), we related plasma GDF15 (Olink) to incident ACD (N=35,673, 14-year follow-up, M age =61±5), vascular dementia (VaD) and Alzheimer’s disease dementia (AD). Finally, we examined the cross-sectional association of plasma GDF15 (SomaScan) with brain volume (N=994), white matter lesions (N=911), and plasma biomarker levels (Aβ 42/40 , GFAP, NfL, and pTau-181) in cognitively normal Baltimore Longitudinal Study of Aging (BLSA) participants. Analyses were stratified by APOEε4 status, cardiometabolic diseases, education, sex, race, and obesity. Late-life GDF15 abundance was associated with ACD risk in the full ARIC sample (HR=1.61 per log 2 increase; [95% CI: 1.36-1.90]) and in all but one subgroup – obese individuals (Figure 1A-B). GDF15 measured during late-life predicted 7-year ACD risk with an AUC of 0.63 (AUC for GDF15+Age: 0.71). Midlife GDF15 was also associated with ACD risk in the full ARIC sample (HR=1.55 per log 2 increase; [1.32-1.82]) and in each subgroup (Figure 1C-D). GDF15 measured during midlife predicted 20-year ACD risk with an AUC of 0.65 (AUC for GDF15+Age: 0.75). We replicated GDF15’s relationship with ACD risk in the UKB sample and found that GDF15 has a much stronger association with VaD (HR=1.76 per log 2 increase; [1.48-2.10]) compared to AD (HR=1.11; [1.01-1.23]; Figure 1E). In the BLSA, higher GDF15 was significantly associated with lower total and regional brain volume, a pattern of accelerated structural brain aging (SPARE-BA), and elevated plasma NfL and pTau181 (Figure 2A-G). Plasma GDF15 is associated with incident dementia risk across multiple cohorts, particularly vascular dementia, independent of cardiometabolic diseases and obesity. While our analyses indicate that GDF15 may play a role in dementia risk as early as midlife, GDF15, alone, provided only modest accuracy for dementia prediction.

Statins are prescribed to lower LDL cholesterol. Clinical guidelines recommend 30–50

Objectives C282Y genetic homozygosity is the main cause of the iron-overload disorder haemochromatosis. Musculoskeletal pain and arthropathy are common in haemochromatosis, but less is known about chondrocalcinosis (cartilage calcification) with the C282Y variant, especially in the community. We assessed knee chondrocalcinosis in intelligent dual-energy X-ray absorptiometer (iDXA) images from UK Biobank volunteers by HFE genotype. Methods Data were from 236 European genetic ancestry C282Y homozygotes and 236 age, sex, and body mass index (BMI)-matched controls with no C282Y alleles (48-80 years, mean 64.6, SD ±7.6). Of 472 participants, 435 had relevant left and right knee iDXA imaging. Evidence of chondrocalcinosis was assessed by an experienced reporting radiographer blind to genotype to ensure unbiased and objective evaluation. Logistic regression models were age, sex, and BMI matched. Results C282Y homozygotes had significantly increased odds of knee chondrocalcinosis (odds ratio [OR]: 3.79, 95% CI: 1.51-9.55, P = .005). Among males, 15.9% (14/88) of homozygotes showed chondrocalcinosis vs <5.9% (<5/84) of controls (OR = 7.76, 95% CI: 1.71-35.25, P = .008). Of affected males, 57.1% reported knee pain, yet fewer than 28.6% had a haemochromatosis diagnosis. In females, 6.0% (8/134) of homozygotes had chondrocalcinosis vs <3.9% (<5/129) of controls, but the association was not statistically significant (OR = 1.98, 95% CI: 0.58-6.76, P = .27), suggesting a need for larger samples. Conclusions In this community-genotyped sample, male C282Y homozygotes had markedly increased odds of knee chondrocalcinosis. Evaluation of serum ferritin levels to identify possible haemochromatosis may be justified in knee chondrocalcinosis management.

Background: Brain iron in specific subcortical regions increases risk of dementia and Parkinson's disease (PD). Genetic and environmental factors affect iron deposition, but underlying mechanisms are unclear. Objective; Identify risk factors and diseases associated with brain iron; assess causality using genetics. Methods: 41,581 UK Biobank participants had MRI-estimated brain iron (QSM method) in five dementia or PD-associated subcortical regions (caudate, hippocampus, putamen, substantia nigra, thalamus). We investigated common risk factors (including adiposity, blood pressure, health behaviors, inflammation) and diseases observationally, using covariate-adjusted regression models, and genetically, with Mendelian randomization. Results: Participants diagnosed with Alzheimer's disease, PD, or other diseases had higher MRI-estimated brain iron. Anemia, osteoporosis, and hyperparathyroidism were associated with lower brain iron. Higher body mass index and blood pressure, smoking history, and self-reported meat consumption, increased brain iron. Hematological parameters, inflammatory and kidney biomarkers, and calcium, were also associated. Genetics support causal effects of depression, type-2 diabetes, and 7 other diseases with increased iron, but not Alzheimer's disease. Evidence supports a causal effect of osteoporosis on lower iron in the substantia nigra. We found causal associations between adiposity and proteins (including IL-6 receptor and transferrin receptor) on subcortical brain iron. Conclusions: We identified causal effects for liability to type-2 diabetes, depression, and other conditions, on subcortical MRI-estimated brain iron, but not to Alzheimer's disease, supportive of dementia as a consequence of brain iron deposition, not a cause. The role of adiposity reducing interventions on brain iron should be investigated. Relationships between brain iron, osteoporosis, calcium, and hyperparathyroidism warrant further investigation.

Background: Hypertension and type 2 diabetes (T2D) are two of the most frequently co-occurring long-term conditions, but their shared mechanisms are not fully understood, often being attributed to adiposity pathways. Here, we aimed to identify shared genetic mechanisms independent of adiposity. Methods: We performed genome-wide association study meta-analyses of T2D and, separately, hypertension. We investigated the bidirectional causal relationship using Mendelian randomisation and quantified genetic correlation before and after accounting for common modifiable risk factors. We then applied a Bayesian GWAS approach to re-estimate SNP-disease effects after accounting for the causal genetic effects of adiposity-related traits. Colocalisation analysis identified shared causal genetic variants, and we investigated the biological pathways involved. Results: We observed a bidirectional causal relationship, and substantial genetic correlation between the two traits (rg = 0.48, 95%CI 0.45-0.52), which persisted after accounting for the genetic contributions of BMI, waist-hip ratio (WHR), and triglycerides (rg = 0.29, 95%CI 0.24-0.34). This indicated shared mechanisms beyond those captured by standard measures of adiposity. We found 98 genetic loci containing variants significantly associated with both hypertension and T2D; colocalisation analysis identified 37 that contained specific shared causal variants. Of these, eight remained statistically significant after adjusting for genetic measures of adiposity, and four were identified only after removing the causal effect of adiposity measures. Shared variants include an allele within PCSK7 associated with risk of both T2D and hypertension and with circulating PCSK7 protein levels, as well as a variant in the 3′ untranslated region of ZNF101 , within the TM6SF2 locus, likely reflecting regulatory variation affecting hepatic lipid metabolism and cardiometabolic traits.

BACKGROUND:Multimorbidity, the presence of two or more conditions in one person, is common but studies are often limited to observational data and single datasets. We address this gap by integrating large-scale primary-care and genetic data from multiple studies to interrogate multimorbidity patterns and producing digital resources to support future research. METHODS:We defined chronic, common, and heritable conditions in individuals aged ≥65 years, using two large primary-care databases [CPRD (UK) N = 2,425,014 and SIDIAP (Spain) N = 1,053,640], and estimated heritability using the same definitions in UK Biobank (N = 451,197). We used logistic regression to estimate the co-occurrence of pairs of conditions in the primary care data. Linkage disequilibrium score regression was used to estimate genetic similarity between pairs of conditions. Meta-analyses were conducted across databases, and up to three sources of genetic data, for each pair of conditions. We classified pairs of conditions as across or within-domain based on the international classification of disease. FINDINGS:We identified 72 chronic conditions, with 43.6% of 2546 pairs showing higher co-occurrence than chance in primary care and evidence of shared genetics. Many across-domain pairs exhibited substantial shared genetics (e.g., iron deficiency anaemia and peripheral arterial disease: genetic correlation Rg = 0.45 [95% Confidence Intervals 0.27:0.64]). 33 pairs displayed negative genetic correlations, such as skin cancer and rheumatoid arthritis (Rg = -0.14 [-0.21:-0.06]), due to potential adverse drug effects. Discordance between genetic and primary care data was also observed, e.g., abdominal aortic aneurysm and bladder cancer co-occurred in primary care but were not genetically correlated (Odds-Ratio = 2.23 [2.09:2.37], Rg = 0.04 [-0.20:0.28]) and schizophrenia and fibromyalgia were less likely to co-occur together in primary care but were positively genetically correlated (OR = 0.84 [0.75:0.94], Rg = 0.20 [0.11:0.29]). INTERPRETATION:Most pairs of chronic conditions show evidence of shared genetics, and co-occurrence in primary care, suggesting shared mechanisms. The identified patterns of shared genetics, negative correlations and discordance between genetic and observational data provide a foundation for future multimorbidity research. FUNDING:UK Medical Research Council [MR/W014548/1].

Supplementary Table from Hereditary Hemochromatosis Variant Associations with Incident Nonliver Malignancies: 11-Year Follow-up in UK Biobank

The mechanisms linking a history of major depressive disorder (MDD) to an increased risk of Alzheimer's disease and related dementia (ADRD) are not fully understood. Using the UK Biobank, we evaluated the biological mechanisms linking both conditions. In participants without history of MDD, 493 proteins were significantly associated with the risk of ADRD. In contrast, in participants with a history of MDD at baseline, a smaller set of 6 proteins were significantly associated ADRD risk (NfL, GFAP, PSG1. VGF, GET3, and HPGDS), with GET3 being specifically associated with ADRD risk in the latter group. Two-sample Mendelian randomization analysis ahowed that the APOE and IL-10 receptor subunit B genes were causally linked to incident ADRD. Finally, we developed a Proteomic Risk Score (PrRSMDD-ADRD), which showed strong discriminative power (C-statistic = 0.84) to identify participants with MDD who developed ADRD upon follow-up. Here we show that plasma proteins associated with inflammation and amyloid-β metabolism are causally linked to a higher ADRD risk in individuals with MDD. Moreover, the PrRSMDD-ADRD can be useful to identify individuals with the highest risk of developing ADRD in a highly vulnerable population.