Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity and mortality. Here we developed a proteomic age clock in the UK Biobank (n = 45,441) using a proteomic platform comprising 2,897 plasma proteins and explored its utility to predict major disease morbidity and mortality in diverse populations. We identified 204 proteins that accurately predict chronological age (Pearson r = 0.94) and found that proteomic aging was associated with the incidence of 18 major chronic diseases (including diseases of the heart, liver, kidney and lung, diabetes, neurodegeneration and cancer), as well as with multimorbidity and all-cause mortality risk. Proteomic aging was also associated with age-related measures of biological, physical and cognitive function, including telomere length, frailty index and reaction time. Proteins contributing most substantially to the proteomic age clock are involved in numerous biological functions, including extracellular matrix interactions, immune response and inflammation, hormone regulation and reproduction, neuronal structure and function and development and differentiation. In a validation study involving biobanks in China (n = 3,977) and Finland (n = 1,990), the proteomic age clock showed similar age prediction accuracy (Pearson r = 0.92 and r = 0.94, respectively) compared to its performance in the UK Biobank. Our results demonstrate that proteomic aging involves proteins spanning multiple functional categories and can be used to predict age-related functional status, multimorbidity and mortality risk across geographically and genetically diverse populations.

Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the associations of alcohol consumption with 207 diseases in the 12-year China Kadoorie Biobank of >512,000 adults (41% men), including 168,050 genotyped forALDH2-rs671andADH1B-rs1229984, with >1.1 million ICD-10 coded hospitalized events. At baseline, 33% of men drank alcohol regularly. Among men, alcohol intake was positively associated with 61 diseases, including 33 not defined by the World Health Organization as alcohol-related, such as cataract (n = 2,028; hazard ratio 1.21; 95% confidence interval 1.09–1.33, per 280 g per week) and gout (n = 402; 1.57, 1.33–1.86). Genotype-predicted mean alcohol intake was positively associated with established (n = 28,564; 1.14, 1.09–1.20) and new alcohol-associated (n = 16,138; 1.06, 1.01–1.12) diseases, and with specific diseases such as liver cirrhosis (n = 499; 2.30, 1.58–3.35), stroke (n = 12,176; 1.38, 1.27–1.49) and gout (n = 338; 2.33, 1.49–3.62), but not ischemic heart disease (n = 8,408; 1.04, 0.94–1.14). Among women, 2% drank alcohol resulting in low power to assess associations of self-reported alcohol intake with disease risks, but genetic findings in women suggested the excess male risks were not due to pleiotropic genotypic effects. Among Chinese men, alcohol consumption increased multiple disease risks, highlighting the need to strengthen preventive measures to reduce alcohol intake.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

In China, alcohol consumption has increased significantly in recent decades. Little evidence exists, however, about temporal trends in levels and patterns of alcohol consumption and associated factors in adult populations. In 2004–08, the China Kadoorie Biobank recruited ~ 512,000 adults (41% men, mean age 52 years [SD 10.7]) from 10 (5 urban, 5 rural) geographically diverse regions across China, with ~ 25,000 randomly selected participants resurveyed in 2013–14. The self-reported prevalence and patterns (e.g., amount, beverage type, heavy drinking episodes) of alcohol drinking at baseline and resurvey were compared and related to socio-demographic, health and other factors. At baseline, 33% of men drank alcohol at least weekly (i.e., current regular), compared to only 2% of women. In men, current regular drinking was more common in urban (38%) than in rural (29%) areas at baseline. Among men, the proportion of current regular drinkers slightly decreased at resurvey (33% baseline vs. 29% resurvey), while the proportion of ex-regular drinkers slightly increased (4% vs. 6%), particularly among older men, with more than half of ex-regular drinkers stopping for health reasons. Among current regular drinkers, the proportion engaging in heavy episodic drinking (i.e., > 60 g/session) increased (30% baseline vs. 35% resurvey) in both rural (29% vs. 33%) and urban (31% vs. 36%) areas, particularly among younger men born in the 1970s (41% vs. 47%). Alcohol intake involved primarily spirits, at both baseline and resurvey. Those engaging in heavy drinking episodes tended to have multiple other health-related risk factors (e.g., regular smoking, low fruit intake, low physical activity and hypertension). Among Chinese men, the proportion of drinkers engaging in harmful drinking behaviours increased in the past decade, particularly among younger men. Harmful drinking patterns tended to cluster with other unhealthy lifestyles and health-related risk factors.

Genetic variants that affect alcohol use in East Asian populations could help assess the causal effects of alcohol consumption on cause-specific mortality. We aimed to investigate the associations between alcohol intake and cause-specific mortality using conventional and genetic epidemiological methods among more than 512 000 adults in China. The prospective China Kadoorie Biobank cohort study enrolled 512 724 adults (210 205 men and 302 519 women) aged 30-79 years, during 2004-08. Residents with no major disabilities from ten diverse urban and rural areas of China were invited to participate, and alcohol use was self-reported. During 12 years of follow-up, 56 550 deaths were recorded through linkage to death registries, including 23 457 deaths among 168 050 participants genotyped for ALDH2-rs671 and ADH1B-rs1229984. Adjusted hazard ratios (HRs) for cause-specific mortality by self-reported and genotype-predicted alcohol intake were estimated using Cox regression. 33% of men drank alcohol most weeks. In conventional observational analyses, ex-drinkers, non-drinkers, and heavy drinkers had higher risks of death from most major causes than moderate drinkers. Among current drinkers, each 100 g/week higher alcohol intake was associated with higher mortality risks from cancers (HR 1·18 [95% CI 1·14-1·22]), cardiovascular disease (CVD; HR 1·19 [1·15-1·24]), liver diseases (HR 1·51 [1·27-1·78]), non-medical causes (HR 1·15 [1·08-1·23]), and all causes (HR 1·18 [1·15-1·20]). In men, ALDH2-rs671 and ADH1B-rs1229984 genotypes predicted 60-fold differences in mean alcohol intake (4 g/week in the lowest group vs 255 g/week in the highest). Genotype-predicted alcohol intake was uniformly and positively associated with risks of death from all causes (n=12 939; HR 1·07 [95% CI 1·05-1·10]) and from pre-defined alcohol-related cancers (n=1274; 1·12 [1·04-1·21]), liver diseases (n=110; 1·31 [1·02-1·69]), and CVD (n=6109; 1·15 [1·10-1·19]), chiefly due to stroke (n=3285; 1·18 [1·12-1·24]) rather than ischaemic heart disease (n=2363; 1·06 [0·99-1·14]). Results were largely consistent using a polygenic score to predict alcohol intake, with higher intakes associated with higher risks of death from alcohol-related cancers, CVD, and all causes. Approximately 2% of women were current drinkers, and although power was low to assess observational associations of alcohol with mortality, the genetic evidence suggested that the excess risks in men were due to alcohol, not pleiotropy. Higher alcohol intake increased the risks of death overall and from major diseases for men in China. There was no genetic evidence of protection from moderate drinking for all-cause and cause-specific mortality, including CVD. Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Wellcome Trust, Medical Research Council, and Chinese Ministry of Science and Technology.

Observational epidemiologic studies have reported that low plasma concentrations of high-density lipoprotein (HDL) cholesterol are an independent risk factor for occlusive cardiovascular disease (CVD), including coronary heart disease (CHD) and ischemic stroke.^1,2 Given these associations, therapeutic strategies to reduce CVD risk by increasing HDL cholesterol concentrations have attracted considerable interest. One such approach is through pharmacologic inhibition of cholesterol ester transfer protein (CETP), which transfers esterified cholesterol from HDL to apolipoprotein B–containing lipoproteins, including very low-density lipoprotein (VLDL), in exchange for triglycerides.³ The first CETP inhibitor assessed in phase 3 trials, torcetrapib, was associated with increased CVD risk, probably owing to off-target effects.^4,5 Subsequent trials of dalcetrapib (which had only modest effects on HDL cholesterol) or evacetrapib (which increased HDL cholesterol levels substantially and lowered LDL cholesterol levels) were stopped early for futility after 2 to 3 years of treatment in high-risk individuals.^6,7 A trial of the potent CETP inhibitor anacetrapib (which doubled HDL cholesterol levels and lowered non-HDL cholesterol levels by about one-fifth) that involved approximately 30 000 high-risk individuals treated for 4 years recently reported a benefit for risk of major coronary events consistent with the effects of lowering non-HDL cholesterol levels.⁸