Type 2 diabetes (T2D) is a highly heritable, polygenic disease with over 600 loci identified through genome-wide association studies (GWAS). However, despite possessing unique genetic variation shaped by demographic history and admixture, Latin American populations remain markedly underrepresented in global genomic research. To address this gap, we conducted genome- and exome-wide analyses of 19,431 T2D cases and 105,611 controls from the Mexico City Prospective Study (MCPS). We identified 86 independent GWAS associations, including 21 novel signals, 15 of which replicated in external cohorts. Risk alleles at novel loci were enriched in individuals with Indigenous American ancestry. Exome analyses revealed rare and ultra-rare missense variants with substantial risk effects at HNF1A and GCK , as well as a protein-damaging variant in SLC30A8 that reduced T2D risk by 45% in carriers. Integrative analyses indicate that T2D genetic architecture in Mexico is predominantly driven by common regulatory variation acting in the endocrine pancreas. Polygenic risk scores strongly stratified T2D risk and transferred to Indigenous Mexican populations. These findings demonstrate the power of large-scale genetic discovery in diverse populations to refine disease architecture and identify loci with potential therapeutic relevance.

Rare coding variants that alter protein function and confer beneficial health effects can suggest potential drug targets. CHRNB3 encodes the β3 subunit of nicotinic acetylcholine receptors that bind nicotine and mediate its action in the brain. Here we report an exome-wide association study of number of cigarettes smoked per day (cig per day) in 37,897 current smokers from the Mexico City Prospective Study. We identify a deleterious missense variant in CHRNB3, p.Glu284Gly, that associates with a significant reduction in daily cigarette consumption. The missense variant is enriched in people of Indigenous Mexican ancestry but rare in other ancestries. We further identify a predicted loss-of-function variant in CHRNB3 that significantly associates with reduction in number of smoked cigarettes per day in participants of Japan Biobank. This variant is enriched in people of East Asian ancestry but is rare in other ancestries. Finally, we find that rare deleterious missense and predicted loss-of-function variants in aggregate associate with a reduction in the number of smoked cigarettes per day in individuals of European ancestry from the UK Biobank. Our results suggest that loss of function of CHRNB3 significantly associates with daily cigarette smoking, proposing β3 inhibition as a potential therapeutic strategy for nicotine addiction.

RATIONALE & OBJECTIVE:Chronic kidney disease (CKD) is a major cause of death in Mexico and blood pressure (BP) may be an important contributor. This study investigated the associations of BP with CKD, albuminuria, and death from kidney failure. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:133,470 adults aged ≥35 to <85 years without CKD or other chronic disease (except diabetes), recruited from two districts of Mexico City between 1998 and 2004, and who survived ≥5 years after recruitment. A random subset of 9198 underwent additional evaluation 2015-2019. EXPOSURES:Systolic BP (SBP), diastolic BP (DBP) and hypertension (participant report of taking blood pressure lowering medication or BP ≥140/90 mm Hg). OUTCOMES:Kidney failure mortality during follow-up, and CKD (self-report and/or eGFR <60 mL/min/1.73m2) and albuminuria at the time of repeat clinical evaluation. ANALYTICAL APPROACH:Multivariable Cox regression for the association of BP with kidney failure mortality and multivariable logistic regression for the association of baseline BP with CKD and albuminuria at the time of re-evaluation. RESULTS:Among all participants, SBP showed a continuous "log-linear" association with kidney failure mortality; each 20 mm Hg lower SBP being associated with 24% lower risk at ages 40-84 years (kidney failure death hazard ratio [HR] 0.76, 95% confidence interval 0.69-0.84). The association was stronger among those without diabetes (HR 0.54, 0.45-0.69) than with diabetes (HR 0.90, 0.80-1.01) but the absolute excess risk associated with higher BP was similar in these subgroups. Hypertension accounted for 9% of kidney failure deaths. Among those re-evaluated, 6% had developed CKD and 25% had albuminuria. 20 mm Hg lower baseline SBP was associated with 24% lower odds of both CKD (odds ratio [OR] 0.76, 0.68-0.85) and albuminuria (OR 0.76, 0.68-0.84) at the time of re-evaluation. Results were similar for DBP. LIMITATIONS:Baseline urine samples were unavailable and kidney function trends over time could not be assessed. CONCLUSIONS:This large prospective study in Mexican adults highlights elevated BP as a major modifiable risk factor for kidney failure mortality, CKD, and albuminuria.

BACKGROUND:Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy. OBJECTIVES:The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD. METHODS:We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies. RESULTS:In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets. CONCLUSIONS:The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.

OBJECTIVE:The Mexican population experiences a notably high prevalence of type 2 diabetes (T2D) and high T2D-associated disease risks. We used targeted plasma nuclear magnetic resonance metabolomics data within a Mendelian randomization framework to characterize the metabolomic profile of genetically predicted liability to T2D in this population. RESEARCH DESIGN AND METHODS:Between 1998 and 2004, 50,000 men and 100,000 women aged ≥35 years were recruited from Mexico City. Mendelian randomization analyses used a genetic risk score (GRS) comprising 1,055 established T2D-associated risk variants and eight pathway-specific T2D GRSs constructed from nonoverlapping subsets of these variants to estimate associations with 143 metabolic biomarkers (including lipids, lipoproteins, fatty acids, amino acids, ketone bodies, and other low-molecular-weight biomarkers). RESULTS:Among 125,587 included participants, the T2D GRS explained 6.0% of T2D liability and was not associated with major potential confounders of the relationships of T2D with the circulating metabolome. Genetically predicted liability to T2D was strongly positively associated with concentrations of VLDL particles and lipids within these, with triglycerides, branched-chain amino acids, and glycoprotein acetyls, and more modestly positively associated with intermediate-density lipoprotein and LDL, particularly small LDL, particles. Inverse associations were found with relative concentrations of several fatty acids. Pathway-specific T2D GRSs all associated with higher T2D risk but showed differential relationships with circulating metabolic biomarkers. CONCLUSIONS:T2D is associated with widespread changes in the circulating metabolome among adults in Mexico, reflecting diverse biological mechanisms and highlighting the importance of effective T2D management, including control of T2D-associated dyslipidemia, in this population.

AIMS:Most polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from European ancestry populations. This paper evaluates the performance of CHD PRSs in a Mexican population. METHODS AND RESULTS:133 207 participants aged 35-79 years from the Mexico City Prospective Study were included. Eight PRSs (comprising 44-6 472 620 polymorphisms) were selected for prediction of CHD (defined as self-reported prior heart attack or angina, or CHD death before age 80 years). Logistic regression was adjusted for age, sex, and the first seven genetic principal components, before and after adjustment for other cardiovascular risk factors. The area under the receiving operating characteristic curve ('C-statistic') was also estimated. Of the included participants, 67% were women, the mean (±SD) age was 51 ± 12 years, and Indigenous American ancestry averaged 67%. CHD was documented for 5163 participants (3.9%), including 1901 prevalent and 3479 fatal cases. All eight PRSs were positively and log-linearly associated with CHD, with odds ratios (ORs) per 1 SD PRS increase ranging from 1.05 (95% CI, 1.03-1.08) to 1.29 (95% CI, 1.25-1.33). Associations were consistent across strata of age and ancestry and were independent of other vascular risk factors. For six PRSs, however, associations were substantially stronger in men than women. Multi-ancestry PRSs outperformed Eurocentric-ancestry PRSs. Despite remaining predictive of risk independently of established non-genetic risk factors, inclusion of a PRS into a risk model did not increase the C-statistic noticeably. CONCLUSION:In this Mexican population, existing PRSs predicted CHD independently of established vascular risk factors, particularly for men. PRSs better capturing genetic variation in Latin American people may further enhance risk prediction in such populations.

Altered energy metabolism is a shared driver across cardiometabolic diseases-the leading cause of death globally1. Energy metabolism varies between individuals and is partly heritable2-9. Here, to investigate the genetic basis of energy metabolism, we perform an exome-sequencing analysis of 1,032,116 people from America, Europe and Asia, and estimate associations between rare protein-coding variants and the ratio of triglyceride to high-density-lipoprotein cholesterol (TG:HDL)-an energy-state biomarker that we associate with diverse cardiometabolic risk factors and diseases. We identify 59 independent genes (P < 1.04 × 10-7) that are enriched for liver- and adipose-expressed master regulators of energy balance, storage and metabolism; 23 (39%) of these genes encode approved or clinical-stage drug targets. Ultra-rare protein-truncating variants in FNIP1 (allele frequency, 0.01%), which encodes a suppressor of energy expenditure and mitochondrial metabolism, are associated with a lower TG:HDL ratio, lower liver fat, lower glycaemia, favourable fat distribution and around 60% lower odds of cardiometabolic disease. FNIP1 knockdown in primary human hepatocytes induces lipid breakdown and lysosomal gene expression, while combined hepatic knockdown of Fnip1 with its paralogue Fnip2 or knockdown of its interactor Flcn protect against weight gain, reduce liver fat and enhance insulin sensitivity in mice fed a high-fat diet. Our study implicates the FNIP1 pathway in human energy metabolism and highlights its inhibition as a potential therapeutic strategy in cardiometabolic disease.

Rationale & Objective:Reduced kidney function is strongly associated with higher mortality, but most evidence is from high-income populations. This study evaluated the relevance of kidney function to cause-specific mortality in Mexico, a country where diabetes is common and chronic kidney disease (CKD) is a major cause of morbidity and mortality. Study Design:Prospective study of Mexican adults aged ≥35 years at recruitment (1998-2004) who were followed until October 2022. Setting & Participants:Participants recruited into the Mexico City Prospective Study. Analyses focused on 126,245 participants aged 35-74 years at recruitment without prior disease (except diabetes or CKD). Exposures:Estimated glomerular filtration rate (eGFR). Outcomes:Cause-specific mortality. Analytical Approach:Cox regression was used to relate eGFR to cause-specific mortality. Analyses were adjusted for sociodemographic and lifestyle factors, anthropometry, and diabetes. Results:Among 40,996 men and 85,249 women aged 35-74 years, median eGFR was 102 (IQR, 91-110) mL/min/1.73 m2, mean body mass index was 29.1 (SD 4.9) kg/m2, 1% had self-reported CKD, 13% had previously diagnosed diabetes, and 12,590 died at ages 35-74 years over a median follow-up of 20.4 years. For those with eGFR <105 mL/min/1.73 m2, each 15-mL/min/1.73 m2 lower eGFR was associated with 32% higher all-cause mortality (RR, 1.32; 95% CI, 1.30-1.35). The strongest associations were for kidney (RR, 1.75; 95% CI, 1.69-1.80), infective (RR, 1.34; 95% CI, 1.24-1.44), and vascular deaths (RR, 1.28; 95% CI, 1.24-1.33). Compared with participants with eGFR 90-104 mL/min/1.73 m2, those with eGFR <30 mL/min/1.73 m2 had almost 7 times the all-cause mortality rate (RR, 6.5; 95% CI, 5.7-7.3). For participants with eGFR >105 mL/min/1.73 m2, higher eGFR was associated with higher mortality. The absolute excess mortality risk associated with reduced eGFR was particularly high for those with diabetes. Limitations:Data on urinary albumin and nonfatal disease outcomes were unavailable. Conclusions:In Mexico, decreased kidney function is strongly associated with premature mortality, mainly from vascular, kidney, and infective causes. Prevention and management of CKD, particularly in individuals with diabetes, should be central to disease-prevention policies.

BACKGROUND:Elevated plasma levels of Lp(a) [lipoprotein(a)] are a causal risk factor for coronary heart disease and stroke in European individuals, but the causal relevance of Lp(a) for different stroke types and in East Asian individuals with different Lp(a) genetic architecture is uncertain. METHODS:We measured plasma levels of Lp(a) in a nested case-control study of 18 174 adults (mean [SD] age, 57 [10] years; 49% female) in the China Kadoorie Biobank (CKB) and performed a genome-wide association analysis to identify genetic variants affecting Lp(a) levels, with replication in ancestry-specific subsets in UK Biobank. We further performed 2-sample Mendelian randomization analyses, associating ancestry-specific Lp(a)-associated instrumental variants derived from CKB or from published data in European individuals with risk of myocardial infarction (n=17 091), ischemic stroke (IS [n=29 233]) and its subtypes, or intracerebral hemorrhage (n=5845) in East Asian and European individuals using available data from CKB and genome-wide association analysis consortia. RESULTS:In CKB observational analyses, plasma levels of Lp(a) were log-linearly and positively associated with higher risks of myocardial infarction and IS, but not with intracerebral hemorrhage. In genome-wide association analysis, we identified 29 single nucleotide polymorphisms independently associated with Lp(a) that together explained 33% of variance in Lp(a) in Chinese individuals. In UK Biobank, the lead Chinese variants identified in CKB were replicated in 1260 Chinese individuals, but explained only 10% of variance in Lp(a) in European individuals. In Mendelian randomization analyses, however, there were highly concordant effects of Lp(a) across both ancestries for all cardiovascular disease outcomes examined. In combined analyses of both ancestries, the proportional reductions in risk per 100 nmol/L lower genetically predicted Lp(a) levels for myocardial infarction were 3-fold greater than for total IS (rate ratio, 0.78 [95% CI, 0.76-0.81] versus 0.94 [0.92-0.96]), but were similar to those for large-artery IS (0.80 [0.73-0.87]; n=8134). There were weaker associations with cardioembolic IS (0.92 [95% CI, 0.86-0.98]; n=11 730), and no association with small-vessel IS (0.99 [0.91-1.07]; n=12 343) or with intracerebral hemorrhage (1.08 [0.96-1.21]; n=5845). CONCLUSIONS:The effects of Lp(a) on risk of myocardial infarction and large-artery IS were comparable in East Asian and European individuals, suggesting that people with either ancestry could expect comparable proportional benefits for equivalent reductions in Lp(a), but there was little effect on other stroke types.

BACKGROUND:Observational studies relating blood pressure in middle age to mortality may underestimate lifelong effects. Mendelian randomization can reduce the impact of confounding and reverse causality and may better estimate lifelong effects of blood pressure on mortality. METHODS:Mendelian randomization analyses used 125 895 Mexico City Prospective Study participants aged 35 to 74 years at recruitment with valid genetic and other data. Cox regression, adjusted for confounders and regression dilution bias, related blood pressure to mortality in 133 027 participants aged 35 to 74 years without prior chronic disease (other than diabetes) at recruitment. RESULTS:In the genetic analyses (40 560 [32%] men; mean age 50 years, mean body mass index 29 kg/m2) there were 13 153 deaths before age 75 years (3478 cardiovascular, 2053 kidney, and 7622 other). Each 10 mm Hg higher genetically predicted lifelong systolic blood pressure was associated with 73% higher cardiovascular mortality at ages 35 to 74 years (rate ratio, 1.73 [95% CI, 1.44-2.06]), 42% higher kidney death (1.42 [95% CI, 1.15-1.75]), but no clear increase in death from other causes. These lifelong rate ratios were higher than those estimated by observational analyses relating blood pressure in middle age to risk. Mendelian randomization analyses of lifelong diastolic blood pressure confirmed strong associations with cardiovascular but not kidney death. Mortality rate ratios were similar for men and women and in those with versus without diabetes, and broadly similar at different ages and at different proportions of Indigenous American ancestry. Sensitivity analyses gave consistent results. CONCLUSIONS:In this Mexican population, genetically informed lifelong differences in blood pressure were strongly related to death from cardiovascular and kidney disease.

To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P < 1x10(-8)), and CHEK2 at the suggestive threshold (P < 2.6x10(-6)). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75-3.83], P = 1.35x10(-6)), as well as confirming the role of BRCA2 in determining disease severity. At the single-variant level, our study reveals that a rare missense variant in TERT is associated with substantially reduced prostate cancer risk (OR = 0.13 [0.07-0.25], P = 4.67x10(-10)), and confirms rare non-synonymous variants in a further three genes associated with reduced risk (ANO7, SPDL1, AR) and in three with increased risk (HOXB13, CHEK2, BIK). Altogether, this work provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity, with potential implications for clinical risk prediction and therapeutic strategies.

The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10-185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10-19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.

UK Biobank is a large-scale prospective study with extensive genetic and phenotypic data from half a million adults. Participants, aged 40 to 69, were recruited from the general UK population between 2006 and 2010. During recruitment, participants completed questionnaires covering lifestyle and medical history, underwent physical measurements, and provided biological samples for long-term storage. Whole-cohort assays have been conducted, including biochemical markers, genotyping, whole-exome and whole-genome sequencing, as well as proteomics and metabolomics in large subsets of the cohort, with potential for additional assays in the future. Participants consented to link their data to electronic health records, enabling the identification of health outcomes over time. Research studies using UK Biobank data have already enhanced our understanding of the role of genetic variation in neurologic disease, offering insights into potential therapeutic approaches. The integration of genetic and imaging data has led to significant discoveries regarding the relationship between genetic variants and brain structure and function, particularly in Alzheimer disease and Parkinson disease. Genetic data have also allowed Mendelian randomization analyses to be performed, enabling further investigation into the causality of associations between behavioral and physiologic factors-such as diet and blood pressure-and neurologic outcomes. Furthermore, genetic and proteomic data have been particularly useful in identifying new drug targets for neurologic disease and in enhancing risk prediction algorithms that are increasingly applied in clinical practice to identify those at higher risk. As UK Biobank continues to be enhanced, and the cases of neurologic disease accrue over time, the study will become increasingly valuable for both discovery and translational research on genetics and neurologic disease.

Background:Observational epidemiological studies in Mexico have shown high mortality risks associated with type 2 diabetes (T2D). However, it is unclear whether these relationships are wholly causal. We aimed to assess the association of genetically-predicted T2D liability with risk of death in Mexico. Methods:Between 1998 and 2004, 150,000 men and women were recruited from Mexico City and followed-up until September 2022 for cause-specific mortality. Mendelian randomisation analyses, using a genetic risk score (GRS) comprising 1055 established T2D-associated risk variants, estimated associations with risk of all-cause and cause-specific mortality at ages 35-74. Findings:Among 121,433 included participants with a mean (standard deviation) age of 51 (11), 68% (n = 82,249) were women and 18% (n = 21,371) had T2D. The GRS explained 6.3% of T2D liability and was not associated with major potential confounders of the T2D-mortality relationship. During a median (interquartile range) of 20.2 (19.4-21.4) years' follow-up, 12,293 participants died. Genetically-predicted T2D liability was associated with a death rate ratio (RR) of 1.29 (95% confidence interval [CI] 1.23-1.36) per trebling in genetically-predicted odds of T2D. There were particularly strong associations with death from renal disease (n = 1696; RR 2.29 [95% CI 1.99-2.64]) and acute diabetic crises (n = 509; RR 2.27 [1.75-2.93]) and weaker, but still strong, associations with death from vascular disease (n = 3226; RR 1.31 [1.19-1.46]) and infection (n = 2437; RR 1.21 [1.07-1.36]). Genetically-predicted T2D liability was not clearly associated with death from cancer (n = 2016; RR 1.00 [95% CI 0.88-1.14]) or cirrhosis (n = 895; RR 0.90 [0.74-1.10]). Interpretation:T2D is causally associated with death from vascular, renal and infectious diseases. Its prevention and effective management could substantially reduce premature deaths in Mexico, where T2D is common. Funding:Wellcome Trust, the Mexican Health Ministry, the National Council for Science and Technology (CONACyT) for Mexico, Cancer Research UK, British Heart Foundation, Kidney Research UK, UK Medical Research Council, AstraZeneca, Regeneron.

UK Biobank is a large‐scale, prospective study with extensive genetic and phenotypic data on half a million individuals. Volunteers, aged between 40 and 69 years, were recruited between 2006 and 2010 from the general population of the United Kingdom. At recruitment, participants completed a series of questionnaires on a range of factors (including lifestyle and medical history), physical measurements were taken and biological samples were collected for long‐term storage. Large‐scale assays have been undertaken (including biochemical assays, genotyping, whole exome and whole genome sequencing, as well as proteomics and metabolomics) with potential for further assays to be performed on stored samples in the future. The participants provided consent for linkage to their health‐related records to identify health outcomes over time. The UK Biobank study, with its vast collection of genetic data, has enabled researchers worldwide to identify new drug targets for common diseases of middle and older age, and progress towards precision medicine. As the UK Biobank resource matures, its value to health‐related research will continue to grow. Thousands of researchers worldwide are actively using UK Biobank data to improve our understanding of the prevention, diagnosis and treatment of a wide range of diseases.

BACKGROUND:Persistent hyperglycaemia in diabetes can cause weight loss, distorting the association of adiposity with mortality. We estimated the lifelong associations of genetically predicted body mass index (BMI) with 52 causes of death among 125 003 Mexican adults, in whom persistent hyperglycaemia in diabetes was common. METHODS:A trans-ancestry genetic instrument for BMI (from 724 BMI-associated single-nucleotide polymorphisms) estimated the causal relevance of BMI to mortality before age 75 years, stratified by sex and adjusted for age and underlying ancestry structure, using a one-sample Mendelian randomization (MR) approach. Two-sample MR and other sensitivity analyses were also performed. RESULTS:The genetic instrument explained 3% of the BMI variation and predicted BMI similarly in men and women. Each 5-kg/m2 higher genetically predicted BMI was associated with nearly a doubling in the risk of all-cause mortality at ages 35-74 years [13 066 deaths; hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.63-2.00]. Hazard ratios were greater for vascular-metabolic (n =  7111; HR 2.15, 95% CI 1.87-2.48) than for non-vascular-metabolic causes (n =  5955; HR 1.47, 95% CI 1.27-1.71) and particularly strong for renal (n =  2034; HR 3.59, 95% CI 2.76-4.67), acute diabetic crises (n =  557; HR 2.70, 95% CI 1.64-4.44), and infective deaths (n =  811; HR 2.61, 95% CI 1.73-3.92). For all-cause mortality, HRs were somewhat greater at younger ages compared with older ages, and slightly larger in those with a higher proportion of Indigenous American ancestry. The strength of the association with mortality was reduced by more than half after simple adjustment for genetic predisposition to diabetes. Sensitivity analyses supported the main conclusions. CONCLUSION:In this Mexican population, genetically predicted lifelong BMI was strongly related to mortality and mediated substantially through diabetes.

Human populations differ in disease prevalences and in average values of phenotypes, but the extent to which differences are caused by genetic or environmental factors is unknown for most complex traits. Comparing phenotypic means across populations is confounded by environmental differences and comparisons based on polygenic predictors can lead to biased inference. Family-based analyses of genetically admixed individuals offer a powerful framework for disentangling the direct and associated effects of genetic ancestry on phenotypes. Here, we leverage genetic data from admixed adults in the Mexico City Prospective Study (MCPS) to estimate within-family ancestry effects. We quantified associations between genetic ancestry and 15 complex traits among 52,583 unrelated individuals and in 39,714 relatives across 17,627 families. At the population level, relative to a European ancestry baseline, we estimate an effect of Indigenous American (IAM) ancestry of -1.98 standard deviations (P < 2×10-16) for height and a natural log-odds ratio (lnOR) of 1.73 (95% confidence interval [CI] 1.54-1.92) for type 2 diabetes (T2D, P < 2×10-16), and multiple associations with other traits and ancestries. We estimated a within-family direct effect of IAM of -1.51 standard deviations (P = 1.02×10-8) for height and lnOR of 5.13 (95% CI 2.48-7.78, P = 1.51×10-4) for risk of T2D. These direct effects are supported by between-ancestry differences in polygenic burden and evidence of selection at trait-associated loci. In contrast, we found no evidence for a direct effect of ancestry on educational attainment or other study traits despite large and significant associations at the population level, implying environmental causes or confounding. Overall, this study provides an experimental design to study between- ancestry genetic effects for complex traits and reports significant ancestry differences for height, T2D, and metabolic-related traits in a genetically diverse population from Mexico City. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by funding from the Mexican Health Ministry; the National Council for Science and Technology (CONACyT) for Mexico; the Wellcome Trust [058299/Z/99]; Cancer Research UK; the British Heart Foundation [RE/13/1/30181]; and the UK Medical Research Council [MC\_UU\_00017/2, MR/Z504543/1]. Genotyping was supported through an academic partnership involving the National Autonomous University of Mexico, the University of Oxford, Regeneron Pharmaceuticals, and AstraZeneca. No authors received payment from a pharmaceutical company or other agency for writing this article. ### 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: Ethics approval was obtained from the Mexican Ministry of Health, the Mexican National Council for Science and Technology, and the University of Oxford, 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 All data produced in the present study are available upon reasonable request to the authors