NGFN-PLUS
Evaluation of candidate genes for obesity and related disorders
| Coordinator: | Prof. Dr. Thomas Illig | |
| Institution: | Medizinische Hochschule Hannover (former Helmholtz Zentrum München) | |
| Homepage: | www.helmholtz-muenchen.de |
WB 2a Evaluation of candidate genes for obesity and related disorders in large representative epidemiological cohorts encompassing children and adults
Coordinator: Prof. Dr. Thomas Illig, Medizinische Hochschule Hannover
Within WB2 we validated potential obesity DNA variants. In this context Helmholtz Zentrum München acted as genotyping platform for KORA surveys, GINI, LISA, and the children studies from Berlin, Datteln and Ulm. We were also extending the validation and detection of potential obesity genes in a genome wide methylation profiling approach. Uni Regensburg is a permanent active member of the GIANT consortium providing close contact for NGFN members as well as contributing extensively in all running projects. Further, together with WB1 partners we developed strategies for fine-mapping, re-sequencing, and Assessment of developmental and longitudinal aspects, of clinical relevance and gene-gene and gene-environment interactions.
In several large scale GWAs as well as replication approaches we contributed to the identification of so far 63 loci for T2D as well as 2 sex specific loci within the DIAbetes Genetics Replication And Meta-analysis Consortium (DIAGRAM) (Voight et al., Nat Genet, 2010, Morris et al., Nat Genet, 2012). The underlying disease mechanisms are still not fully understood, but the identified genes seem to be concentrated in few key processes like cell cycle regulation, adipocytokine signaling and CREBBP-related Transcription factor activity. Similarly, we also contributed to the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), which could identify 36 risk loci for fasting glucose, 19 for fasting insulin and 9 for 2 h glucose (Dupuis et al., Nat Genet., 2010, Scott et al., Nat Genet., 2012).
Within the GIANT (Genetic Investigation of ANthropometric Traits)-Consortium we contributed to the identification of 32 risk variants, which impact body weight regulation. Single risk variants or combinations of them can account for differences in body weight between 130 g and 1.5 kg (Speliotes et al., Nat Genet. 2010). Comparing 5% individuals with highest BMI against 5% with the lowest BMI (‚body mass index‘) of the total available individuals resulted in identification of 7 additional risk variants for obesity (Berndt et al., Nat Genet. 2013). A sex stratified analysis on anthropometric traits yielded 7 hits with significant sex-difference 6 women-specific loci without any effect in men, including 3 novel (near MAP3K1, HSD17B4, PPARG) and 3 previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA) loci and one previously published locus (near ADAMTS9) with a less pronounced effect in men (Randall et al., Plos Genet., 2013).
Besides genome wide approaches we supported several candidate studies within WB2a, which gave deeper insights in the specific relationships (see publication list). Validated genes as well as potential methylated sites were functionally characterized in WB3.
WB 2b Implications of obesity intervention with interaction of allelic variations in obese children and adolescents
Coordinator: PD Dr. Thomas Reinehr, Institut für Pädiatrische Ernährungsmedizin Vestische Kinder- und Jugendklinik, Universität Witten/Herdecke
This subproject is aimed to identify the impact of different genetic variants on the long-term success over 3 years in a 1-year outpatient obesity intervention program based on physical exercise, nutrition education, and behaviour therapy including the individual psychological care of the child and his/her family. This lifestyle intervention has been proven to achieve weight maintenance in the majority of the participations even after the end of intervention. So far, little is known about the medium and long-term implications of weight cycling. Therefore, analysis of long-term implications of weight cycling on phenotypic, physiological, and molecular parameters was performed in this project. Identification of genetic variants with lower or higher success rates and with the occurrence of weight cycling during or after intervention will help to adapt the intervention to specific groups and to study the impact of different genetic variants on the human weight loss management. Furthermore, the changes of adipocytokines after obesity intervention were investigated in relation to the genetic profile.
The DAPOC study („Obeldicks“) was genotyped for several projects. Based on these results 10 SNPs close to 5 genes, which show influence on body weight were analyzed in 401 obese children of the DAPOC study concerning longitudinal changes of weight status (SDS-BMI) and insulin resistance (HOMA). 3 SNPs in introns 6, 9 and 10 of the SDCCAG8 gene showed an effect with reduction of overweight adjusted for age sex and multiple testing (Scherag 2012). These results could not be replicated in obese adults with hypercaloric diet.
In collaboration with the Helmoltz Zentrum München metabolite profiles from 80 obese and 40 normal weight children from the lifestyle intervention study obeldicks were generated. After Bonferroni-correction 14 metabolites and 69 metabolite ratios showed significant differences between the two groups. Especially conspicuous were differences in Phosphatidylcholine-, Aminoacidsand fattyacid metabolism (Wahl 2012). Trying to identify pre-intervention determinants of weight loss two metabolites and waist circumference seem to predict weight loss during intervention, with lower values in children with substantial weight loss (Wahl 2013).
Analyzing the effects of obesity risk genes NEGR1, TNKS, SDCCAG8, FTO, MC4R, TMEM18, PTER, MTCH2, SH2B1, MAF, NPC1, und KCTD15 on weight regain after a lifestyle intervention in overweight children, there was no evidence for effects of any of the GWAS-based obesity marker alleles on weight regain in the course of 1 year after an intervention (Hinney accepted).
Study details:
- 1412 obese children and adolescence (5-7 years)
Available markers:
- Body fat markers (waist-to-hip ratio, wrinkles size, bio impedance analysis)
- Insulin resistance (oGTT, Insulin, glucose, HOMA-index)
Cardiovascular risk factors (blood pressure, liver enzymes, lipids, uric acid)
Longitudinal data in life style intervention:
- 815 children and adolescence with baseline data and 1 year follow-up
- 505 children with 2 year follow-up
The subproject is linked to Work Block (WB) 4 (therapy) of the research pipeline and WB1 (gene identification) and WB2b (Weight regulation under certain clinical settings, weight regulation in extreme obesity).
WB 2c RECALL
Coordinator: Prof. Dr. Susanne Moebus, Institut für Medizinische Informatik, Biometrie und Epidemiologie, Universität Duisburg-Essen
Meta-analyses of population-based genome-wide association studies (GWAS) in adults have led to the detection of new genetic loci for Body-mass-index variability and obesity. As a subproject TP15b the network initiated a GWAS meta-analysis to discover additional obesity loci in extremely obese children and adolescents. In WB2-Recall it was tested if the results from the (extreme) obese children and adolescents are also applicable to the adult general population. Our subproject contributed ten selected single nucleotide polymorphisms (SNPs) genotyped in 4,646 Heinz Nixdorf Recall participants. The study revealed three known (FTO, MC4R and TMEM18) and two new loci (SDCCAG8 and TNKS/MSRA). The study concluded that the currently known major common variants related to obesity overlap to a substantial degree between children and adults (1).
The development of both diabetes mellitus and subclinical atherosclerosis is characterized by a presumed early onset. Since individuals with diabetes are at high risk for coronary heart disease (CHD), we examined the association between 11 diabetes related SNP derived for diabetes mellitus GWAS and the extent of coronary artery calcification (CAC) in 4,459 Heinz Nixdorf Recall study participants. CAC is one of the most sensitive and a specific marker of coronary atherosclerotic plaque burden and is an important risk factor for myocardial infarction and sudden cardiac death. We found a strong association of CAC and a genetic variant near CDKN2A/2B. Interestingly this variant has been reported to be strongly associated with diabetes. In contrast, variants near IGFBP2, CDKAL1, SLC30A8, HHEX, and TCF7L2 were clearly associated with diabetes, but not with CAC. This differential association pattern underlines the potential of endophenotypes, such as CAC, to extend the scope of disease outcome associations (2).
Extending our search for possible associations of genetic variants with CAC, we used the data of the Metabochip for the 4,570 Heinz Nixdorf Recall participants. The study demonstrated that SNPs near 9p21 and in the PHACTR1 gene that have previously been shown to be associated with CHD are strongly associated with CAC. Our findings suggest that the 9p21and 6p24 loci might be involved in cardiac outcome via promoting development of atherosclerosis in the coronary arteries (3).
Reference List
(1) Scherag A, Dina C, Hinney A et al. Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups. PLoS Genet 2010 April;6(4):e1000916.
(2) Pechlivanis S, Scherag A, Muhleisen TW et al. Coronary artery calcification and its relationship to validated genetic variants for diabetes mellitus assessed in the Heinz Nixdorf recall cohort. Arterioscler Thromb Vasc Biol 2010 September;30(9):1867-72.
(3) Pechlivanis S, Muhleisen TW, Mohlenkamp S et al. Risk loci for coronary artery calcification replicated at 9p21 and 6q24 in the Heinz Nixdorf Recall Study. BMC Med Genet 2013;14:23.
Further Coordinators:
Coordinator: Prof. Dr. Thomas Illig, Medizinische Hochschule Hannover
Within WB2 we validated potential obesity DNA variants. In this context Helmholtz Zentrum München acted as genotyping platform for KORA surveys, GINI, LISA, and the children studies from Berlin, Datteln and Ulm. We were also extending the validation and detection of potential obesity genes in a genome wide methylation profiling approach. Uni Regensburg is a permanent active member of the GIANT consortium providing close contact for NGFN members as well as contributing extensively in all running projects. Further, together with WB1 partners we developed strategies for fine-mapping, re-sequencing, and Assessment of developmental and longitudinal aspects, of clinical relevance and gene-gene and gene-environment interactions.
In several large scale GWAs as well as replication approaches we contributed to the identification of so far 63 loci for T2D as well as 2 sex specific loci within the DIAbetes Genetics Replication And Meta-analysis Consortium (DIAGRAM) (Voight et al., Nat Genet, 2010, Morris et al., Nat Genet, 2012). The underlying disease mechanisms are still not fully understood, but the identified genes seem to be concentrated in few key processes like cell cycle regulation, adipocytokine signaling and CREBBP-related Transcription factor activity. Similarly, we also contributed to the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), which could identify 36 risk loci for fasting glucose, 19 for fasting insulin and 9 for 2 h glucose (Dupuis et al., Nat Genet., 2010, Scott et al., Nat Genet., 2012).
Within the GIANT (Genetic Investigation of ANthropometric Traits)-Consortium we contributed to the identification of 32 risk variants, which impact body weight regulation. Single risk variants or combinations of them can account for differences in body weight between 130 g and 1.5 kg (Speliotes et al., Nat Genet. 2010). Comparing 5% individuals with highest BMI against 5% with the lowest BMI (‚body mass index‘) of the total available individuals resulted in identification of 7 additional risk variants for obesity (Berndt et al., Nat Genet. 2013). A sex stratified analysis on anthropometric traits yielded 7 hits with significant sex-difference 6 women-specific loci without any effect in men, including 3 novel (near MAP3K1, HSD17B4, PPARG) and 3 previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA) loci and one previously published locus (near ADAMTS9) with a less pronounced effect in men (Randall et al., Plos Genet., 2013).
Besides genome wide approaches we supported several candidate studies within WB2a, which gave deeper insights in the specific relationships (see publication list). Validated genes as well as potential methylated sites were functionally characterized in WB3.
WB 2b Implications of obesity intervention with interaction of allelic variations in obese children and adolescents
Coordinator: PD Dr. Thomas Reinehr, Institut für Pädiatrische Ernährungsmedizin Vestische Kinder- und Jugendklinik, Universität Witten/Herdecke
This subproject is aimed to identify the impact of different genetic variants on the long-term success over 3 years in a 1-year outpatient obesity intervention program based on physical exercise, nutrition education, and behaviour therapy including the individual psychological care of the child and his/her family. This lifestyle intervention has been proven to achieve weight maintenance in the majority of the participations even after the end of intervention. So far, little is known about the medium and long-term implications of weight cycling. Therefore, analysis of long-term implications of weight cycling on phenotypic, physiological, and molecular parameters was performed in this project. Identification of genetic variants with lower or higher success rates and with the occurrence of weight cycling during or after intervention will help to adapt the intervention to specific groups and to study the impact of different genetic variants on the human weight loss management. Furthermore, the changes of adipocytokines after obesity intervention were investigated in relation to the genetic profile.
The DAPOC study („Obeldicks“) was genotyped for several projects. Based on these results 10 SNPs close to 5 genes, which show influence on body weight were analyzed in 401 obese children of the DAPOC study concerning longitudinal changes of weight status (SDS-BMI) and insulin resistance (HOMA). 3 SNPs in introns 6, 9 and 10 of the SDCCAG8 gene showed an effect with reduction of overweight adjusted for age sex and multiple testing (Scherag 2012). These results could not be replicated in obese adults with hypercaloric diet.
In collaboration with the Helmoltz Zentrum München metabolite profiles from 80 obese and 40 normal weight children from the lifestyle intervention study obeldicks were generated. After Bonferroni-correction 14 metabolites and 69 metabolite ratios showed significant differences between the two groups. Especially conspicuous were differences in Phosphatidylcholine-, Aminoacidsand fattyacid metabolism (Wahl 2012). Trying to identify pre-intervention determinants of weight loss two metabolites and waist circumference seem to predict weight loss during intervention, with lower values in children with substantial weight loss (Wahl 2013).
Analyzing the effects of obesity risk genes NEGR1, TNKS, SDCCAG8, FTO, MC4R, TMEM18, PTER, MTCH2, SH2B1, MAF, NPC1, und KCTD15 on weight regain after a lifestyle intervention in overweight children, there was no evidence for effects of any of the GWAS-based obesity marker alleles on weight regain in the course of 1 year after an intervention (Hinney accepted).
Study details:
- 1412 obese children and adolescence (5-7 years)
Available markers:
- Body fat markers (waist-to-hip ratio, wrinkles size, bio impedance analysis)
- Insulin resistance (oGTT, Insulin, glucose, HOMA-index)
Cardiovascular risk factors (blood pressure, liver enzymes, lipids, uric acid)
Longitudinal data in life style intervention:
- 815 children and adolescence with baseline data and 1 year follow-up
- 505 children with 2 year follow-up
The subproject is linked to Work Block (WB) 4 (therapy) of the research pipeline and WB1 (gene identification) and WB2b (Weight regulation under certain clinical settings, weight regulation in extreme obesity).
WB 2c RECALL
Coordinator: Prof. Dr. Susanne Moebus, Institut für Medizinische Informatik, Biometrie und Epidemiologie, Universität Duisburg-Essen
Meta-analyses of population-based genome-wide association studies (GWAS) in adults have led to the detection of new genetic loci for Body-mass-index variability and obesity. As a subproject TP15b the network initiated a GWAS meta-analysis to discover additional obesity loci in extremely obese children and adolescents. In WB2-Recall it was tested if the results from the (extreme) obese children and adolescents are also applicable to the adult general population. Our subproject contributed ten selected single nucleotide polymorphisms (SNPs) genotyped in 4,646 Heinz Nixdorf Recall participants. The study revealed three known (FTO, MC4R and TMEM18) and two new loci (SDCCAG8 and TNKS/MSRA). The study concluded that the currently known major common variants related to obesity overlap to a substantial degree between children and adults (1).
The development of both diabetes mellitus and subclinical atherosclerosis is characterized by a presumed early onset. Since individuals with diabetes are at high risk for coronary heart disease (CHD), we examined the association between 11 diabetes related SNP derived for diabetes mellitus GWAS and the extent of coronary artery calcification (CAC) in 4,459 Heinz Nixdorf Recall study participants. CAC is one of the most sensitive and a specific marker of coronary atherosclerotic plaque burden and is an important risk factor for myocardial infarction and sudden cardiac death. We found a strong association of CAC and a genetic variant near CDKN2A/2B. Interestingly this variant has been reported to be strongly associated with diabetes. In contrast, variants near IGFBP2, CDKAL1, SLC30A8, HHEX, and TCF7L2 were clearly associated with diabetes, but not with CAC. This differential association pattern underlines the potential of endophenotypes, such as CAC, to extend the scope of disease outcome associations (2).
Extending our search for possible associations of genetic variants with CAC, we used the data of the Metabochip for the 4,570 Heinz Nixdorf Recall participants. The study demonstrated that SNPs near 9p21 and in the PHACTR1 gene that have previously been shown to be associated with CHD are strongly associated with CAC. Our findings suggest that the 9p21and 6p24 loci might be involved in cardiac outcome via promoting development of atherosclerosis in the coronary arteries (3).
Reference List
(1) Scherag A, Dina C, Hinney A et al. Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups. PLoS Genet 2010 April;6(4):e1000916.
(2) Pechlivanis S, Scherag A, Muhleisen TW et al. Coronary artery calcification and its relationship to validated genetic variants for diabetes mellitus assessed in the Heinz Nixdorf recall cohort. Arterioscler Thromb Vasc Biol 2010 September;30(9):1867-72.
(3) Pechlivanis S, Muhleisen TW, Mohlenkamp S et al. Risk loci for coronary artery calcification replicated at 9p21 and 6q24 in the Heinz Nixdorf Recall Study. BMC Med Genet 2013;14:23.
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