The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health ...care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.
Successful efforts to stem the rise in obesity and type 2 diabetes will require a detailed understanding of the genetic and environmental factors affecting individuals as well as a broad consideration of societal challenges, including responses to COVID-19, faced by communities across the globe.
Past studies identified rare copy number variants (CNVs) as risk factors for neurodevelopmental disorders (NDDs), including autism spectrum disorder and schizophrenia. However, the clinical ...characterization of NDD CNVs is understudied in population cohorts unselected for neuropsychiatric disorders and in cohorts of diverse ancestry.
To identify individuals harboring NDD CNVs in a multiancestry biobank and to query their enrichment for select neuropsychiatric disorders as well as association with multiple medical disorders.
In a series of phenotypic enrichment and association analyses, NDD CNVs were clinically characterized among 24 877 participants in the BioMe biobank, an electronic health record-linked biobank derived from the Mount Sinai Health System, New York, New York. Participants were recruited into the biobank since September 2007 across diverse ancestry and medical and neuropsychiatric specialties. For the current analyses, electronic health record data were analyzed from May 2004 through May 2019.
NDD CNVs were identified using a consensus of 2 CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by novel in-silico clinical assessments.
Of 24 877 participants, 14 586 (58.7%) were female; self-reported ancestry categories included 5965 (24.0%) who were of African ancestry, 7892 (31.7%) who were of European ancestry, and 8536 (34.3%) who were of Hispanic ancestry; and the mean (SD) age was 50.5 (17.3) years. Among 24 877 individuals, the prevalence of 64 NDD CNVs was 2.5% (n = 627), with prevalence varying by locus, corroborating the presence of some relatively highly prevalent NDD CNVs (eg, 15q11.2 deletion/duplication). An aggregate set of NDD CNVs were enriched for congenital disorders (odds ratio, 2.0; 95% CI, 1.1-3.5; P = .01) and major depressive disorder (odds ratio, 1.5; 95% CI, 1.1-2.0; P = .01). In a meta-analysis of medical diagnoses (n = 195 hierarchically clustered diagnostic codes), NDD CNVs were significantly associated with several medical outcomes, including essential hypertension (z score = 3.6; P = 2.8 × 10-4), kidney failure (z score = 3.3; P = 1.1 × 10-3), and obstructive sleep apnea (z score = 3.4; P = 8.1 × 10-4) and, in another analysis, morbid obesity (z score = 3.8; P = 1.3 × 10-4). Further, NDD CNVs were associated with increased body mass index in a multiancestry analysis (β = 0.19; 95% CI, 0.10-0.31; P = .003). For 36 common serum tests, there was no association with NDD CNVs.
Clinical features of individuals harboring NDD CNVs were elucidated in a large-scale, multiancestry biobank, identifying enrichments for congenital disorders and major depressive disorder as well as associations with several medical outcomes, including hypertension, kidney failure, and obesity and obesity-related phenotypes, specifically obstructive sleep apnea and increased body mass index. The association between NDD CNVs and obesity outcomes indicate further potential pleiotropy of NDD CNVs beyond neurodevelopmental outcomes previously reported. Future clinical genetic investigations may lead to insights of at-risk individuals and therapeutic strategies targeting specific genetic variants. The importance of diverse inclusion within biobanks and considering the effect of rare genetic variants in a multiancestry context is evident.
The timing of associations between common genetic variants for weight or body mass index (BMI) across the life course may provide insights into the aetiology of obesity. We genotyped variants in FTO ...(rs9939609) and near MC4R (rs17782313) in 1240 men and 1239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2–20 years) or adulthood (20–53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; 95% CI: 0.003–0.010, P < 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele, 0.08–0.19), and then weakened during adulthood (−0.003 SDS/A-allele/year, −0.005 to −0.001, P = 0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; 0.001–0.008, P = 0.006), peaked at age 20 years (0.13 SDS/C-allele, 0.07–0.18), and weakened during adulthood (−0.002 SDS/C-allele/year, −0.004 to 0.000, P = 0.05). In conclusion, genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. Studies of the aetiology of obesity spanning different age groups may identify age-specific determinants of weight gain.
Common Variants in CDKAL1 , CDKN2A/B , IGF2BP2 , SLC30A8 , and HHEX/IDE Genes Are Associated With Type 2 Diabetes and Impaired Fasting Glucose in a Chinese Han Population
Ying Wu 1 ,
Huaixing Li 1 ,
...Ruth J.F. Loos 2 ,
Zhijie Yu 1 ,
Xingwang Ye 1 ,
Lihua Chen 1 ,
An Pan 1 ,
Frank B. Hu 3 and
Xu Lin 1
1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China
2 Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K
3 Department of Nutrition, Harvard School of Public Health, Harvard University, Boston, Massachusetts
Corresponding author: Dr. Xu Lin, xlin{at}sibs.ac.cn
Abstract
OBJECTIVE— Genome-wide association studies have identified common variants in CDKAL1 , CDKN2A/B , IGF2BP2 , SLC30A8 , HHEX/IDE , EXT2 , and LOC387761 loci that significantly increase the risk of type 2 diabetes. We aimed to replicate these observations in a population-based
cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes.
RESEARCH DESIGN AND METHODS— We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type
2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose.
RESULTS— We confirmed the associations between type 2 diabetes and variants near CDKAL1 (odds ratio 1.49 95% CI 1.27–1.75; P = 8.91 × 10 −7 ) and CDKN2A/B (1.31 1.12–1.54; P = 1.0 × 10 −3 ). We observed significant association of SNPs in IGF2BP2 (1.17 1.03–1.32; P = 0.014) and SLC30A8 (1.12 1.01–1.25; P = 0.033) with combined IFG/type 2 diabetes. The SNPs in CDKAL1 , IGF2BP2 , and SLC30A8 were also associated with impaired β-cell function estimated by homeostasis model assessment of β-cell function. When combined,
each additional risk allele from CDKAL1 -rs9465871, CDKN2A/B -rs10811661, IGF2BP2 -rs4402960, and SLC30A8 -rs13266634 increased the risk for type 2 diabetes by 1.24-fold ( P = 2.85 × 10 −7 ) or for combined IFG/type 2 diabetes by 1.21-fold ( P = 6.31 × 10 −11 ). None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG. Significant association was observed between the HHEX/IDE SNPs and type 2 diabetes in individuals from Shanghai only ( P < 0.013) but not in those from Beijing ( P > 0.33).
CONCLUSIONS— Our results indicate that in Chinese Hans, common variants in CDKAL1 , CDKN2A/B , IGF2BP2 , and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through β-cell dysfunction.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008.
Y.W. and H.L. contributed equally to this article.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted July 3, 2008.
Received January 14, 2008.
DIABETES
While rare
MC4R mutations are the commonest cause of monogenic forms of extreme, early-onset obesity, growing evidence shows that common
MC4R variants contribute to obesity in the general population. ...Candidate gene studies have focussed on the V103I and I251L
MC4R variants that both affect MC
4 receptor function
in vitro. Individual association studies, which are typically small and underpowered, have found no association between V103I (frequency of 103I-allele: ~
4%) or I251L (251
L-allele: ~
2%) and the risk of obesity in the general population. However, large-scale meta-analyses have confirmed that both variants reduce the risk of obesity by −
21% in 103I-allele carriers (
P
<
10
−4) and by −
50% in 251
L-allele carriers (
P
<
10
−4). Recently, genome-wide association studies have identified a common variant (minor allele frequency: ~
27%) at ~
188
kb downstream of
MC4R showing robust association (
P
<
5
×
10
−8) with BMI and obesity in adults and children. Each additional minor allele increases BMI by 0.20
kg/m
2, body weight by 700–1000
g, and obesity risk by 14% in adults. Interestingly, this variant also showed association with increased height, consistent with the phenotype seen for rare
MC4R mutations. Although
MC4R is the nearest gene and phenotypic associations are consistent with those of
MC4R mutations, it has not yet been established whether this variant indeed reflects MC
4 receptor function. Taken together, common
MC4R variants contribute to variation in BMI and obesity risk in the general population. Of particular interest is the finding from genome-wide association studies that suggests that the region downstream of
MC4R contributes to its regulation.
Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association ...studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.
Background: Twin and family studies that estimated the heritability of daily physical activity have been limited by poor measurement quality and a small sample size.Objective: We examined the ...heritability of daily physical activity and sedentary behavior assessed objectively by using combined heart rate and movement sensing in a large twin study.Design: Physical activity traits were assessed in daily life for a mean (±SD) 6.7 ± 1.1 d in 1654 twins from 420 monozygotic and 352 dizygotic same-sex twin pairs aged 56.3 ± 10.4 y with body mass index (in kg/m2) of 26.1 ± 4.8. We estimated the average daily movement, physical activity energy expenditure, and time spent in moderate-to-vigorous intensity physical activity and sedentary behavior from heart rate and acceleration data. We used structural equation modeling to examine the contribution of additive genetic, shared environmental, and unique environmental factors to between-individual variation in traits.Results: Additive genetic factors (ie, heritability) explained 47% of the variance in physical activity energy expenditure (95% CI: 23%, 53%) and time spent in moderate-to-vigorous intensity physical activity (95% CI: 29%, 54%), 35% of the variance in acceleration of the trunk (95% CI: 0%, 44%), and 31% of the variance in the time spent in sedentary behavior (95% CI: 9%, 51%). The remaining variance was predominantly explained by unique environmental factors and random error, whereas shared environmental factors played only a marginal role for all traits with a range of 0–15%.Conclusions: The between-individual variation in daily physical activity and sedentary behavior is mainly a result of environmental influences. Nevertheless, genetic factors explain up to one-half of the variance, suggesting that innate biological processes may be driving some of our daily physical activity.
Recently, genome-wide association studies have provided evidence that several common variants within the fat mass-and obesity-associated (FTO) gene were significantly associated with obesity in ...populations of European origin. However, their effects in other ethnic populations remain to be elucidated.
In this study, we examined the association between three FTO variants (rs8050136, rs9939609, and rs9930506) and obesity and related traits in a population-based study of 3,210 unrelated Chinese Han subjects from Shanghai and Beijing. In secondary analyses, we also tested for association with type 2 diabetes and related traits. Logistics regression and generalized linear models were used to test for additive and dominant effects of the risk alleles.
The minor allele frequencies of rs8050136, rs9939609, and rs9930506 in our population (0.12, 0.12, and 0.20, respectively) were substantially lower than those observed for populations of European descent (e.g., for CEU population of HapMap: 0.45, 0.48, and 0.45, respectively). Despite our study being sufficiently powered to detect effects similar to those previously reported, none of the FTO SNPs were found to be associated with obesity, overweight, BMI, waist circumference, or body fat percentage. In addition, none of the SNPs exhibited significant associations with fasting levels of plasma glucose, A1C, insulin, or beta-cell function (estimated via homeostasis model assessment) under either an additive or a dominant model in the quantitative trait analyses. Analyses stratified by sex or geographical region did not change these observations.
Our data do not support that the FTO common variants are major contributors of obesity or type 2 diabetes in the Chinese Han population.
Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we ...report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.
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