Meta-analysis of genome-wide linkage studies of asthma and related traits

Background

Asthma and allergy are complex multifactorial disorders, with both genetic and environmental components determining disease expression. The use of molecular genetics holds great promise for the identification of novel drug targets for the treatment of asthma and allergy. Genome-wide linkage studies have identified a number of potential disease susceptibility loci but replication remains inconsistent. The aim of the current study was to complete a meta-analysis of data from genome-wide linkage studies of asthma and related phenotypes and provide inferences about the consistency of results and to identify novel regions for future gene discovery.

Methods

The rank based genome-scan meta-analysis (GSMA) method was used to combine linkage data for asthma and related traits; bronchial hyper-responsiveness (BHR), allergen positive skin prick test (SPT) and total serum Immunoglobulin E (IgE) from nine Caucasian asthma populations.

Results

Significant evidence for susceptibility loci was identified for quantitative traits including; BHR (989 pedigrees, n = 4,294) 2p12-q22.1, 6p22.3-p21.1 and 11q24.1-qter, allergen SPT (1,093 pedigrees, n = 4,746) 3p22.1-q22.1, 17p12-q24.3 and total IgE (729 pedigrees, n = 3,224) 5q11.2-q14.3 and 6pter-p22.3. Analysis of the asthma phenotype (1,267 pedigrees, n = 5,832) did not identify any region showing genome-wide significance.

Conclusion

This study represents the first linkage meta-analysis to determine the relative contribution of chromosomal regions to the risk of developing asthma and atopy. Several significant results were obtained for quantitative traits but not for asthma confirming the increased phenotype and genetic heterogeneity in asthma. These analyses support the contribution of regions that contain previously identified asthma susceptibility genes and provide the first evidence for susceptibility loci on 5q11.2-q14.3 and 11q24.1-qter.     

Meta-analysis of results from quantitative trait loci mapping studies on pig chromosome 4

Meta-analysis of results from multiple studies could lead to more precise quantitative trait loci (QTL) position estimates compared to the individual experiments. As the raw data from many different studies are not readily available, the use of results from published articles may be helpful. In this study, we performed a meta-analysis of QTL on chromosome 4 in pig, using data from 25 separate experiments. First, a meta-analysis was performed for individual traits: average daily gain and backfat thickness. Second, a meta-analysis was performed for the QTL of three traits affecting loin yield: loin eye area, carcass length and loin meat weight. Third, 78 QTL were selected from 20 traits that could be assigned to one of three broad categories: carcass, fatness or growth traits. For each analysis, the number of identified meta-QTL was smaller than the number of initial QTL. The reduction in the number of QTL ranged from 71% to 86% compared to the total number before the meta-analysis. In addition, the meta-analysis reduced the QTL confidence intervals by as much as 85% compared to individual QTL estimates. The reduction in the confidence interval was greater when a large number of independent QTL was included in the meta-analysis. Meta-QTL related to growth and fatness were found in the same region as the FAT1 region. Results indicate that the meta-analysis is an efficient strategy to estimate the number and refine the positions of QTL when QTL estimates are available from multiple populations and experiments. This strategy can be used to better target further studies such as the selection of candidate genes related to trait variation.     

Tenomodulin is associated with obesity and diabetes risk: the Finnish diabetes prevention study

We recently showed that long-term weight reduction changes the gene expression profile of adipose tissue in overweight individuals with impaired glucose tolerance (IGT). One of the responding genes was X-chromosomal tenomodulin (TNMD), a putative angiogenesis inhibitor. Our aim was to study the associations of individual single nucleotide polymorphisms and haplotypes with adiposity, glucose metabolism, and the risk of type 2 diabetes (T2D). Seven single nucleotide polymorphisms from two different haploblocks were genotyped from 507 participants of the Finnish Diabetes Prevention Study (DPS). Sex-specific genotype effects were observed. Three markers of haploblock 1 were associated with features of adiposity in women (rs5966709, rs4828037) and men (rs11798018). Markers rs2073163 and rs1155794 from haploblock 2 were associated with 2-hour plasma glucose levels in men during the 3-year follow-up. The same two markers together with rs2073162 associated with the conversion of IGT to T2D in men. The risk of developing T2D was approximately 2-fold in individuals with genotypes associated with higher 2-hour plasma glucose levels; the hazard ratios were 2.192 (p = 0.025) for rs2073162-A, 2.191 (p = 0.027) for rs2073163-C, and 1.998 (p = 0.054) for rs1155974-T. These results suggest that TNMD polymorphisms are associated with adiposity and also with glucose metabolism and conversion from IGT to T2D in men.     

Meta‐analysis on the G‐308A Tumor Necrosis Factor α Gene Variant and Phenotypes Associated with the Metabolic Syndrome

Objective: The G‐308A tumor necrosis factor (TNF) α gene variant has been associated with obesity, insulin resistance, and hypertension. We performed a systematical review of the literature by means of a meta‐analysis to assess the association of the G‐308A TNFα polymorphism with the components of the metabolic syndrome. Research Methods and Procedures: Studies were identified by searches of the literature for reports using the terms: diabetes, insulin resistance, hypertension, obesity or metabolic syndrome and TNF, variants or polymorphism or alleles, and Nco or ?308. From 824 reports, we included 31 observational studies, case control and cohort at baseline, which analyzed the association between the TNFα polymorphism and one or more components of the metabolic syndrome. A fixed effect model was used to pool data from individual studies. Results: Obesity [odds ratio, 1.23; 95% confidence interval (CI), 1.045 to 1.45; p = 0.013] in a total of 3562 individuals from eight homogeneous studies, systolic arterial blood pressure (standardized difference, 0.132; 95% CI, 0.016 to 0.25; p < 0.03) in a total of 1624 individuals from four homogeneous studies and plasma insulin levels (standardized difference, 0.095; 95% CI, 0.020 to 0.17; p = 0.013) in a total of 3720 subjects from 16 homogeneous studies were positively associated with the ?308A variant. Discussion: These results indicate that individuals who carried the ?308A TNFα gene variant are at 23% risk of developing obesity compared with controls and showed significantly higher systolic arterial blood pressure and plasma insulin levels, supporting the hypothesis that the TNFα gene is involved in the pathogenesis of the metabolic syndrome.     

Correlates of BMI misreporting among apparently healthy individuals: the ATTICA study

Objective: The aim of this study was to investigate correlates of misreporting in BMI, based on self‐reported weight and height, in a randomly selected population sample of Greek adults and to evaluate the effect of obesity status misclassification on the associations between obesity and disease. Research Methods and Procedures: During 2001 to 2002, we randomly enrolled 1514 men (18 to 87 years old) and 1528 women (18 to 89 years old) from the Attica area, Greece; the sampling was stratified by the age‐sex distribution of the region. Various sociodemographic, clinical, and psychological characteristics were self‐reported, and weight and height were measured and recorded in all participants. Results: The proportions of true positives and true negatives for correct obesity status identification were 62% and 97%, respectively. Women were 9 times more likely to be under‐reporters than men, whereas men were 7.5 times more likely to be over‐reporters. A 10‐year increase in age was associated with a 48% higher likelihood of being an under‐reporter and 26% lower likelihood of being an over‐reporter, irrespective of sex and other characteristics of the participants. Clinical status, such as the presence of hypertension and diabetes, was associated with under‐reporting of body weight. Furthermore, the use of self‐reported data may substantially exaggerate associations between obesity and obesity‐related diseases, such as diabetes, hypercholesterolemia, and hypertension. Discussion: The study indicates that, apart from age and sex, disease status may be another factor that influences misreporting of obesity status, with diabetic and hypertensive people to be more likely to under‐report their overweight. Use of self‐reported data may bias obesity—disease associations.     

Critical reasoning on causal inference in genome-wide linkage and association studies

Genome-wide linkage and association studies of tens of thousands of clinical and molecular traits are currently underway, offering rich data for inferring causality between traits and genetic variation. However, the inference process is based on discovering subtle patterns in the correlation between traits and is therefore challenging and could create a flood of untrustworthy causal inferences. Here we introduce the concerns and show that they are already valid in simple scenarios of two traits linked to or associated with the same genomic region. We argue that more comprehensive analysis and Bayesian reasoning are needed and that these can overcome some of the pitfalls, although not in every conceivable case. We conclude that causal inference methods can still be of use in the iterative process of mathematical modeling and biological validation.     

BMI modifies associations of IL-6 genotypes with insulin resistance: the Framingham Study

Objective: The ?174 interleukin (IL)‐6 gene polymorphism has been proposed as a risk factor for type 2 diabetes, but data are conflicting. Because white fat is a major source of IL‐6 in resting individuals, we tested the hypothesis that BMI modifies the association among the IL‐6 genotype, insulin resistance (IR) (measured using the homeostasis model), and risk of diabetes. Research Methods and Procedures: Outcomes were assessed in a community‐based cohort study of 1525 adults (mean age, 55.6 years; 753 men), who participated in the Framingham Offspring Study during the 1991 to 1995 examinations. Results: We found a significant interaction between IL‐6 genotype and BMI on levels of IR in men (p < 0.0001), with obese homozygotes for the minor C allele being most resistant. The IL‐6‐BMI interaction was not significant (p = 0.46) in women. Among men with the CC genotype, increasing BMI was associated with increased prevalence of diabetes [odds ratio (OR) per unit increase in BMI, 1.30; 95% confidence interval (CI), 1.11 to 1.50] but not among those with the GG (OR, 1.10; 95% CI, 0.98 to 1.22) or GC genotype (OR, 1.05; 95% CI, 0.97 to 1.14). Discussion: The ?174 IL‐6 promoter polymorphism modifies the association of obesity with IR and diabetes risk in men. Weight loss regimens targeted at reducing the risk of diabetes may be of particular benefit for men with a ?174 IL‐6 CC genotype.     

原发性高血压全基因组关联研究进展

原发性高血压是一种由遗传与环境因素共同导致的复杂疾病,具有高度的遗传异质性。自2007年首个高血压全基因组关联研究(Genome-wide association studies,GWAS)报道以来,许多GWAS相继开展。文章首先对2007年1月至2011年9月期间报道的24篇血压/高血压易感基因的GWAS按人种与染色体位置对其结果进行汇总,经统计位点rs17249754、rs1378942和rs11191548报道频数最多。其次介绍了GWAS方法学的研究进展,包括选择高质量的数量表型和选择多阶段研究设计来增加研究发现阳性关联的机会。统计分析方面,除强调了已经报道过的多重比较和重复(验证)研究等问题外,文章还介绍了通过Meta分析对GWAS数据进行深度发掘,并应用基因型填补法对缺失数据进行填补可以提高全基因组遗传标记的覆盖率的方法。尽管GWAS发现了许多我们未知的基因与疾病表型的关联,为了解高血压的发病机制提供了更多线索,但是目前GWAS发现的血压/高血压相关变异多为对人群血压的影响极其微弱的常见变异。因此今后的研究中可加强深度功能学研究对易感基因精细定位和外显子组测序技术的应用,结合GWAS的成果进行生物信息学通路分析和表观遗传学机制研究等,逐步揭示高血压的遗传机制。     

A mother’s legacy: the strength of maternal effects in animal populations

Although mothers influence the traits of their offspring in many ways beyond the transmission of genes, it remains unclear how important such ‘maternal effects’ are to phenotypic differences among individuals. Synthesizing estimates derived from detailed pedigrees, we evaluated the amount of phenotypic variation determined by maternal effects in animal populations. Maternal effects account for half as much phenotypic variation within populations as do additive genetic effects. Maternal effects most greatly affect morphology and phenology but, surprisingly, are not stronger in species with prolonged maternal care than in species without. While maternal effects influence juvenile traits more than adult traits on average, they do not decline across ontogeny for behaviour or physiology, and they do not weaken across the life cycle in species without maternal care. These findings underscore maternal effects as an important source of phenotypic variation and emphasise their potential to affect many ecological and evolutionary processes.     

Association of common polymorphisms in the IL2RA gene with type 1 diabetes: evidence of 32,646 individuals from 10 independent studies

Single nucleotide polymorphisms (SNPs) in the interleukin 2 receptor alpha (IL2RA) gene have been suggested to be associated with type 1 diabetes (T1D) susceptibility. However, the results from individual studies are inconsistent. To explore the association of IL2RA polymorphisms with T1D, including rs11594656, rs2104286, rs3118470, rs41295061 and rs706778, a meta‐analysis involving 10 independent studies with 19 outcomes was conducted: five studies with a total of 10,572 cases and 12,956 controls were analysed for rs11594656 with T1D risk, three studies with 7300 cases and 8331 controls for rs2104286, three studies with 3880 cases and 5409 controls for rs3118470, five studies with 11,253 cases and 13,834 controls for rs41295061 and three studies with 1896 cases and 1709 controls for rs706778 respectively. Using minor allelic comparison, the five investigated SNPs were all observed to have a significant association with T1D: For rs11594656, fixed effect model (FEM) odds ratio (OR) 0.87, 95% confidence interval (CI) 0.83, 0.91; rs2104286, FEM OR 0.81, 95% CI 0.77, 0.85; rs3118470, FEM OR 1.23, 95% CI 1.16, 1.31; rs41295061, random effect model (REM) OR 0.67, 95% CI 0.60, 0.76 and rs706778 FEM OR 1.20, 95% CI 1.08, 1.33. Similar results were obtained when all the included studies were calculated by a REM. Our meta‐analysis suggests that all five SNPs in the IL2RA gene are risk factors for T1D risk, and rs11594656, rs2104286 and rs41295061 are the most associated SNPs in the populations investigated. This conclusion warrants confirmation by further studies.     

Comparative studies of quantitative trait and neutral marker divergence: a meta-analysis

Comparative studies of quantitative genetic and neutral marker differentiation have provided means for assessing the relative roles of natural selection and random genetic drift in explaining among-population divergence. This information can be useful for our fundamental understanding of population differentiation, as well as for identifying management units in conservation biology. Here, we provide comprehensive review and meta-analysis of the empirical studies that have compared quantitative genetic (Q(ST)) and neutral marker (F(ST)) differentiation among natural populations. Our analyses confirm the conclusion from previous reviews - based on ca. 100% more data - that the Q(ST) values are on average higher than F(ST) values [mean difference 0.12 (SD 0.27)] suggesting a predominant role for natural selection as a cause of differentiation in quantitative traits. However, although the influence of trait (life history, morphological and behavioural) and marker type (e.g. microsatellites and allozymes) on the variance of the difference between Q(ST) and F(ST) is small, there is much heterogeneity in the data attributable to variation between specific studies and traits. The latter is understandable as there is no reason to expect that natural selection would be acting in similar fashion on all populations and traits (except for fitness itself). We also found evidence to suggest that Q(ST) and F(ST) values across studies are positively correlated, but the significance of this finding remains unclear. We discuss these results in the context of utility of the Q(ST)-F(ST) comparisons as a tool for inferring natural selection, as well as associated methodological and interpretational problems involved with individual and meta-analytic studies.     

The association between paraoxonase 1 activity and the susceptibilities of diabetes mellitus,diabetic macroangiopathy and diabetic microangiopathy

We carried out this meta‐analysis to explore the influence of paraoxonase 1 activity on the susceptibility of diabetes mellitus (DM), diabetic macroangiopathy and diabetic microangiopathy. Relevant studies were identified from PubMed, Web of Science and CNKI without language limitation, following the inclusion and exclusion criteria. Statistical analyses were implemented with the STATA 12.0 statistical software. Thirty‐six case‐control studies were included in the meta‐analyses, in which 35 for the association between paraoxonase 1 activity and DM risk, 8 for diabetic macroangiopathy and 7 for diabetic microangiopathy. Paraoxonase 1 activity was significantly associated with the susceptibility of DM in pooled population (SMD = ?1.37, 95% CI = ?1.79 ～ ?0.96, P = .000), and Asians (SMD = ?2.00, 95% CI = ?2.56 ～ ?1.44, P = .000), but not in non‐Asians (SMD = ?0.44, 95% CI = ?0.91 ～ 0.03, P = .069). However, marked heterogeneity was existed (I² = 98.10%, P = .000) and subgroup analyses failed to investigate the sources of heterogeneity. Then, meta‐regression was performed and found that ethnicity could explain the observed between‐study heterogeneity (P = .002). Meanwhile, significant associations were found between paraoxonase 1 activity and diabetic macroangiopathy (SMD = ?1.06, 95% CI = ?1.63 ～ ?0.48, P = .000) and diabetic microangiopathy (SMD = ?0.72, 95% CI = ?1.32 ～ ?0.13, P = .018). In conclusion, paraoxonase 1 activity plays important roles in the risk of DM, diabetic macroangiopathy and microangiopathy with ethnicity differences. Further studies with large sample and well design are needed to confirm these results.     

An overview about DNA methylation in childhood obesity: Characteristics of the studies and main findings

Childhood obesity is a global burden affecting millions of children worldwide. It is well-known that the adiposity profile in children is critical for future occurrence of diseases. As a multifactorial disease, obesity is associated with genetic and environmental factors. Epigenetic mechanisms link the plethora of environmental clues to a given phenotype. DNA methylation is the most studied epigenetic mark and its importance in several diseases was acknowledged. In childhood obesity, specifically, the studies show a consistent association between adiposity and methylation at the gene and genome-wide scales. The relationship between DNA methylation and childhood obesity has been proved strong for some genes and pathways. However, the studies are heterogeneous in their design, methodologies, and results. The aim of this review is to discuss this heterogeneity and point out some aspects that should be considered in future studies to clarify the role of DNA methylation in childhood obesity.     

Contribution of genetics to ecological restoration

Ecological restoration of degraded ecosystems has emerged as a critical tool in the fight to reverse and ameliorate the current loss of biodiversity and ecosystem services. Approaches derived from different genetic disciplines are extending the theoretical and applied frameworks on which ecological restoration is based. We performed a search of scientific articles and identified 160 articles that employed a genetic approach within a restoration context to shed light on the links between genetics and restoration. These articles were then classified on whether they examined association between genetics and fitness or the application of genetics in demographic studies, and on the way the studies informed restoration practice. Although genetic research in restoration is rapidly growing, we found that studies could make better use of the extensive toolbox developed by applied fields in genetics. Overall, 41% of reviewed studies used genetic information to evaluate or monitor restoration, and 59% provided genetic information to guide prerestoration decision‐making processes. Reviewed studies suggest that restoration practitioners often overlook the importance of including genetic aspects within their restoration goals. Even though there is a genetic basis influencing the provision of ecosystem services, few studies explored this relationship. We provide a view of research gaps, future directions and challenges in the genetics of restoration.     

Adiposity in Middle‐aged Women is Associated with Genetic Taste Blindness to 6‐n‐Propylthiouracil

Objective: Taste blindness to the bitterness of 6‐n‐propylthiouracil (PROP) may be a genetic marker for food preferences and dietary choices that ultimately influence body weight. A previous study in middle‐aged women showed that those who were taste blind to PROP (i.e., nontasters) had higher BMIs than those with the greatest sensitivity to PROP (i.e., supertasters). This study tested the hypothesis that the nontaster phenotype was associated with greater adiposity in middle‐aged women. Research Methods and Procedures: Forty women with a mean BMI of 26.6 ± 1.3 kg/m² and a mean age of 41.8 ± 1.8 years were recruited from the local community. They were classified as nontasters (n = 8), medium tasters (n = 18), or supertasters (n = 14) of PROP using a filter paper screening procedure. Anthropometric measures included height, weight, body fatness, triceps skinfold thickness, and waist circumference. Dietary restraint and disinhibition were also measured to assess cognitions associated with body weight. Results: BMI was 6.2 units higher in nontaster women compared with supertaster women (29.7 ± 0.9 vs. 23.5 ± 0.9, respectively; p < 0.05). Body fatness (p < 0.01) and triceps skinfold thickness (p < 0.05) were also higher in these women. Waist circumference showed a trend in the appropriate direction. Although disinhibition was associated with greater adiposity, the relation between PROP status and adiposity was not altered after controlling for disinhibition. Discussion: The PROP nontaster phenotype was strongly associated with several measures of adiposity in middle‐aged women. These data confirm our previous findings and suggest that the PROP polymorphism may be a reliable indicator of weight gain susceptibility.     

General quantitative genetic methods for comparative biology: phylogenies,taxonomies and multi‐trait models for continuous and categorical characters

Although many of the statistical techniques used in comparative biology were originally developed in quantitative genetics, subsequent development of comparative techniques has progressed in relative isolation. Consequently, many of the new and planned developments in comparative analysis already have well‐tested solutions in quantitative genetics. In this paper, we take three recent publications that develop phylogenetic meta‐analysis, either implicitly or explicitly, and show how they can be considered as quantitative genetic models. We highlight some of the difficulties with the proposed solutions, and demonstrate that standard quantitative genetic theory and software offer solutions. We also show how results from Bayesian quantitative genetics can be used to create efficient Markov chain Monte Carlo algorithms for phylogenetic mixed models, thereby extending their generality to non‐Gaussian data. Of particular utility is the development of multinomial models for analysing the evolution of discrete traits, and the development of multi‐trait models in which traits can follow different distributions. Meta‐analyses often include a nonrandom collection of species for which the full phylogenetic tree has only been partly resolved. Using missing data theory, we show how the presented models can be used to correct for nonrandom sampling and show how taxonomies and phylogenies can be combined to give a flexible framework with which to model dependence.     

Current opportunities and challenges: genome-wide association studies on pigmentation and skin cancer

Genome-wide association studies (GWAS) have become a widely used approach for genetic association studies of various human traits. A few GWAS have been conducted with the goal of identifying novel loci for pigmentation traits, melanoma, and non-melanoma skin cancer. Nevertheless, the phenotype variation explained by the genetic markers identified so far is limited. In this review, we discuss the GWAS study design and its application in pigmentation and skin cancer research. Furthermore, we summarize recent developments in post-GWAS activities such as meta-analysis, pathway analysis, and risk prediction.     

Effect of obesity on high-density lipoprotein metabolism

Reduced levels of high-density lipoproteins (HDL) in non-obese and obese states are associated with increased risk for the development of coronary artery disease. Therefore, it is imperative to determine the mechanisms responsible for reduced HDL in obese states and, conversely, to examine therapies aimed at increasing HDL levels in these individuals. This paper examines the multiple causes for reduced HDL in obese states and the effect of exercise and diet--two non-pharmacologic therapies--on HDL metabolism in humans. In general, the concentration of HDL-cholesterol is adversely altered in obesity, with HDL-cholesterol levels associated with both the degree and distribution of obesity. More specifically, intra-abdominal visceral fat deposition is an important negative correlate of HDL-cholesterol. The specific subfractions of HDL that are altered in obese states include the HDL2, apolipoprotein A-I, and pre-beta1 subfractions. Decreased HDL levels in obesity have been attributed to both an enhancement in the uptake of HDL2 by adipocytes and an increase in the catabolism of apolipoprotein A-I on HDL particles. In addition, there is a decrease in the conversion of the pre-beta1 subfraction, the initial acceptor of cholesterol from peripheral cells, to pre-beta2 particles. Conversely, as a means of reversing the decrease in HDL levels in obesity, sustained weight loss is an effective method. More specifically, weight loss achieved through exercise is more effective at raising HDL levels than dieting. Exercise mediates positive effects on HDL levels at least partly through changes in enzymes of HDL metabolism. Increased lipid transfer to HDL by lipoprotein lipase and reduced HDL clearance by hepatic triglyceride lipase as a result of endurance training are two important mechanisms for increases in HDL observed from exercise.     

Racial Differences in the Tracking of Childhood BMI to Adulthood

Objective: The possibility that there are racial differences in the patterns of BMI (kilograms per meter squared) change throughout life has not been examined. For example, the high prevalence of obesity among black women could result from a higher prevalence of obesity among black girls or because normal‐weight black girls experience larger BMI increases in adolescence or adulthood than do their white counterparts. Therefore, we examined the tracking of childhood BMI into adulthood in a biracial (36% black) sample. Research Methods and Procedures: Five‐ to 14‐year‐old children (2392) were followed for (mean) 17 years. Childhood overweight was defined as BMI ≥ 95th percentile, and adult obesity was defined as BMI ≥ 30 kg/m². Results: The tracking of childhood BMI differed between whites and blacks. Among overweight children, 65% of white girls vs. 84% of black girls became obese adults, and predictive values among boys were 71% (whites) vs. 82% (blacks). These racial differences reflected contrasting patterns in the rate of BMI change. Although the initial BMI of black children was not higher than that of white children, BMI increases with age were larger among black girls and overweight black boys than among their white counterparts. In contrast, relatively thin (BMI < 50th percentile) white boys were more likely to become overweight adults than were their black counterparts. Discussion: These findings emphasize the black/white differences in BMI changes with age. Because of the adult health consequences of childhood‐onset obesity, early prevention should be given additional emphasis.     

Cut‐off Point of BMI and Obesity‐Related Comorbidities and Mortality in Middle‐Aged Koreans

Objective: The need for a lower BMI to classify overweight in Asian populations has been controversial. Using both disease and mortality outcomes, we investigated whether lower BMI cut‐off points are appropriate for identifying increased health risk in Koreans. Research Methods and Procedures: We conducted a cohort study among 773, 915 men and women from 30 to 59 years old with 8‐ to 10‐year follow‐up periods. Primary outcomes were change of obesity prevalence, obesity‐related disease incidence, and all‐cause mortality. Results: Prevalence of overweight (BMI of 25.0‐29.9) has steadily increased (1.3% annually), whereas obesity (BMI ≥ 30) showed a lower prevalence and only a slight increase (0.1%‐0.2% annually). Our study revealed that dose‐response relationships exist between obesity and related disease incidences (hypertension, type 2 diabetes, and hypercholesterolemia) beginning at lower BMI levels than previously reported. Compared with those in the healthy weight range, Koreans with a BMI ≥ 25 were not at greater risk of hypertension, type 2 diabetes, or hypercholesterolemia than has been reported for whites in similar studies. Obesity‐related all‐cause mortality also did not seem so different from that of whites. Discussion: Our findings did not support the use of a lower BMI cut‐off point for defining overweight in Koreans compared with whites for the purpose of identifying different risks. However, populations with BMI ≥ 25 are rapidly increasing and have substantial risks of diseases. To preempt the rapid increases in obesity and related health problems that are occurring in Western countries, Korea should consider using a BMI of 25 as an action point for obesity prevention and control interventions.