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Frank Geller

Publications and source records attributed to Frank Geller.

At least 19 recordsLinked to original sources
PubMed2025

Polygenic prediction of body mass index and obesity through the life course and across ancestries.

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.

Adolescent↗
PubMed2025

Genome-wide association study of long COVID.

Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.

Humans↗
PubMed2006

Absence of the wild-type allele (192 base pairs) of a polymorphism in the promoter region of the IGF-I gene but not a polymorphism in the insulin gene variable number of tandem repeat locus is associated with accelerated weight gain in infancy.

OBJECTIVE: Our goal was to investigate whether a polymorphism in the insulin-like growth factor I promoter gene (IGF-I, wild-type, 192 base pairs) and in the insulin gene (INS) variable number of tandem repeat locus influence birth weight and weight gain in infancy. PATIENTS AND METHODS: We obtained genomic DNA from 768 children. Exclusion criteria were multiple births, gestational diabetes, maternal diabetes, gestational age <37 weeks, >42 weeks, or unclear, and any condition potentially influencing weight gain. SD scores were calculated and adjusted for gestational age and gender. A gain in SD scores for weight between birth and 1 year >0.67 SD scores was defined as accelerated weight gain. Genotyping was performed by fragment length analysis (IGF-I) and by fragment length analysis after using a restriction enzyme-based assay (INS variable number tandem repeat). RESULTS: Accelerated weight gain was present in 205 of 768 children. IGF-I and INS variable number tandem repeat genotype were not associated with birth weight. The IGF-I 192-base pair allele was less frequent in children with accelerated weight gain and was shown to reduce the risk for accelerated weight gain in a logistic regression model. CONCLUSION: The IGF-I 192-base pair allele may reduce the risk for rapid weight gain in early infancy.

Alleles↗
PubMed2005

The 103I variant of the melanocortin 4 receptor is associated with low serum triglyceride levels.

CONTEXT: The melanocortin 4 receptor (MC4R) is an essential regulator of energy intake and body weight. Recently, the V103I polymorphism of MC4R has been shown to be negatively associated with body mass index. This suggests that serum lipids and blood pressure in individuals carrying the 103I allele might be influenced as well. OBJECTIVE: The objective of this study was to determine whether the most common polymorphism of the MC4R, V103I, affects serum lipid levels and/or blood pressure. DESIGN, SETTING, AND PARTICIPANTS: The study participants were 1173 consecutive patients undergoing cardiac catheterization; they were genotyped for the rs2229616 G-->A substitution at codon 103 (V103I polymorphism) of the MC4R gene. Patients had strictly fasted for at least 12 h before blood samples were drawn. The average age of the patients was 60.9 yr; 72% were males. MAIN OUTCOME MEASURES: The main outcome measures were body mass index, serum lipids, aortic and systolic blood pressure, and MC4R polymorphism V103I. RESULTS: Heterozygous carriers of the 103I allele had significantly lower triglyceride levels than individuals homozygous for the wild-type allele (127 vs. 168 mg/dl mean total triglyceride; P = 0.001 or 0.009 after Bonferroni adjustment for seven tests). No homozygous carriers of the 103I allele were present in the study population. CONCLUSIONS: Our study suggests an influence of MC4R activity on triglyceride levels in cardiovascular patients.

Blood Pressure↗
PubMed2005

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder.

Dysfunction of the central serotonergic system has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). The genetic contribution to the development of OCD is particularly high in early-onset OCD. The aim of this study was to investigate the effect of polymorphic variants in the gene of the novel brain-specific tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in OCD with disease onset in childhood and adolescence. We analysed two common single nucleotide polymorphisms (SNPs) of TPH2 in the putative transcriptional control region and in intron 2 of the TPH2 gene in a unique family-based sample of OCD patients with onset of the disease in childhood and adolescence comprising 71 complete, independent trios. The transmission disequilibrium test was used to determine transmission of alleles and haplotypes from parents to offspring. In this first study of TPH2 in OCD, analysis of the SNPs, rs4570625 and rs4565946, revealed a significant preferential transmission of haplotype G-C to children and adolescents with OCD. Moreover, a trend towards preferential transmission of the C allele of SNP rs4565946 to the patients was found. The genotype relative-risk estimate for homozygous C allele carriers of SNP rs4565946 was 2.58 (95% CI 0.98-6.82). In conclusion, the results link TPH2 variations to the pathogenesis of early-onset OCD and further support the aetiological relevance of 5-HT signalling in OCD.

Adolescent↗
PubMed2005

Lack of support for the association between GAD2 polymorphisms and severe human obesity.

The demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention, and treatment of these conditions. Unequivocal proof of such an association, however, requires independent replication of initial positive findings. Recently, three (-243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2). The association was observed among 188 families (612 individuals) segregating the condition, and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (-243 A>G) were also presented. The gene GAD2 encodes the 65-kDa subunit of glutamic acid decarboxylase-GAD65. In the present study, we attempted to replicate this association in larger groups of individuals, and to extend the functional studies of the -243 A>G SNP. Among 2,359 individuals comprising 693 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the -243 A>G SNP and obesity (OR = 0.99, 95% CI 0.83-1.18, p = 0.89) in the pooled sample. These negative findings were recapitulated in a meta-analysis, incorporating all published data for the association between the -243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90-1.36, p = 0.28) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Moreover, analysis of common haplotypes encompassing the GAD2 locus revealed no association with severe obesity in families with the condition. We also obtained functional data for the -243 A>G SNP that does not support a pathophysiological role for this variant in obesity. Potential confounding variables in association studies involving common variants and complex diseases (low power to detect modest genetic effects, overinterpretation of marginal data, population stratification, and biological plausibility) are also discussed in the context of GAD2 and severe obesity.

Adolescent↗
PubMed2005

Possible genomic imprinting of three human obesity-related genetic loci.

To detect potentially imprinted, obesity-related genetic loci, we performed genomewide parent-of-origin linkage analyses under an allele-sharing model for discrete traits and under a family regression model for obesity-related quantitative traits, using a European American sample of 1,297 individuals from 260 families, with 391 microsatellite markers. We also used two smaller, independent samples for replication (a sample of 370 German individuals from 89 families and a sample of 277 African American individuals from 52 families). For discrete-trait analysis, we found evidence for a maternal effect in chromosome region 10p12 across the three samples, with LOD scores of 5.69 (single-point) and 4.52 (multipoint) for the pooled sample. For quantitative-trait analysis, we found the strongest evidence for a maternal effect (single-point LOD of 2.85; multipoint LOD of 4.01 for body mass index [BMI] and 3.69 for waist circumference) in region 12q24 and for a paternal effect (single-point LOD of 4.79; multipoint LOD of 3.72 for BMI) in region 13q32, in the European American sample. The results suggest that parent-of-origin effects, perhaps including genomic imprinting, may play a role in human obesity.

Adipose Tissue↗
PubMed2005

Human galanin (GAL) and galanin 1 receptor (GALR1) variations are not involved in fat intake and early onset obesity.

The neuropeptide galanin (GAL) is involved in food intake and in fat ingestion. Presumably, these effects are conveyed via the galanin 1 receptor (GALR1). We screened the coding region of GAL (including 444 bp of its promoter region) and GALR1 for mutations using single-strand conformation polymorphism analysis and denaturing HPLC in up to 191 obese children and adolescents and 106 healthy underweight young adults (students). In GAL, we identified 3 novel single nucleotide polymorphisms (SNPs; silent: g.-419T-->C, g.-244G-->A; missense: g.47C-->T: Ala16Val) and one infrequent missense variation (c.253A-->G: Asn85Asp), and in GALR1 2 novel SNPs (silent: c.150C-->T, missense: c.793A-->T: Ile265Phe). To test for an association with obesity, we genotyped 7 SNPs (GAL: g.-244G-->A, g.47C-->T, rs7101947, rs1042577, rs3136540; GALR1: c.150C-->T, c.793A-->T) in up to 322 obese children and adolescents compared with up to 277 healthy underweight and normal weight young adults. Furthermore, we analyzed these SNPs with respect to potential effects on the percentage of energy consumed as fat in obese children and adolescents. Allele and genotype frequencies did not differ among the groups tested. In addition, we performed a pedigree transmission disequilibrium test (PDT) for one SNP (GAL: g.-244G-->A) in 610 (518 independent) obesity-trios (obese child or adolescent and both of its parents). However, the PDT for SNP GAL g.-244G-->A revealed no transmission disequilibrium. We conclude that the analyzed SNPs in GAL and GALR1 do not play a major role in early onset obesity or dietary fat intake in the obese children and adolescents of our study groups.

Adolescent↗
PubMed2005

Preprohypocretin polymorphisms in Parkinson disease patients reporting "sleep attacks".

STUDY OBJECTIVES: Previously, we found a significant association between the dopamine D2 receptor gene polymorphism Taq IA and sudden onset of sleep in patients with Parkinson disease. Here we evaluated the association between the preprohypocretin (-909T/C), (-22C/T), and (-20C/A) polymorphisms and sudden onset of sleep in the same population of patients with Parkinson disease. DESIGN: We conducted an association study analyzing the distribution of preprohypocretin polymorphisms in Germanic, caucasian Parkinson disease patients with and without sudden onset of sleep, matched according to drug therapy, disease duration, sex, and age. SETTING: Movement disorders section at a university hospital. PARTICIPANTS: 132 Parkinson disease patients with sudden onset of sleep and 132 Parkinson disease patients without sudden onset of sleep. INTERVENTIONS: Blood samples were taken from each participant and used for DNA extraction. Polymorphisms were analyzed by established polymerase chain reaction protocols or direct sequencing. MEASUREMENTS AND RESULTS: The variant allele T of the (-909T/C) preprohypocretin polymorphism was more commonly found in Parkinson disease patients with sudden onset of sleep. Statistical analysis showed that there were significant differences in the genotype (P = .024) and allele (P = .018) distribution between both groups. For heterozygous and homozygous carriers of allele T, the genotype relative-risk estimates for the presence of sudden onset of sleep were 2.01 (95% confidence interval: 0.76-5.34) and 2.81 (95% confidence interval: 1.09-7.25), respectively. CONCLUSIONS: Our results show a significant association between the (-909T/C) preprohypocretin polymorphism and sudden onset of sleep in Parkinson disease. However, we could not demonstrate any interaction between the Taq IA and (-909T/C) polymorphisms with respect to the occurrence of sudden onset of sleep, suggesting that multiple genetic factors may contribute to the pathogenesis of this phenomenon.

Alleles↗
PubMed2005

Mutation analysis of the MCHR1 gene in human obesity.

OBJECTIVE: The importance of the melanin-concentrating hormone (MCH) system for regulation of energy homeostasis and body weight has been demonstrated in rodents. We analysed the human MCH receptor 1 gene (MCHR1) with respect to human obesity. DESIGN: This consisted of genomic screening of 13.4 kb encompassing the MCHR1 in extremely obese German children and adolescents and association analyses for two coding single nucleotide polymorphisms (SNPs). To confirm initial positive association results, additional association studies and transmission disequilibrium tests in further German, Danish, French and American samples were conducted. Selected SNPs were investigated using functional in vitro studies and reporter gene assays. METHODS: Single-stranded conformation polymorphism analysis, re-sequencing, PCR-restriction fragment length polymorphism analyses, tetra-primer amplification refractory mutation systems, matrix-assisted laser desorption/ionization time of flight mass spectrometry and reporter gene assays were carried out as well as measuring inositol phosphate formation, inhibition of cAMP formation and activation of p42/44 MAP kinase. RESULTS: We identified 11 infrequent variations and two SNPs in the MCHR1 coding sequence and 18 SNPs (eight novel) in the flanking sequence. Association and transmission disequilibrium with obesity were detected for several SNPs in independent study groups of German obese children and adolescents and controls. In two German samples, encompassing 4056 and 295 individuals, trends towards association with obesity were detected. Findings in a second epidemiological German sample and in Danish, French and American samples were negative. Functional in vitro studies as well as reporter gene assays revealed no significant results. CONCLUSION: Our initial association of MCHR1 alleles/haplotype detected might be related to juvenile-onset obesity, conditional on a particular genetic and/or environmental background. Alternatively, we could not exclude the possibility that the initially detected association represented a false positive finding.

Adolescent↗
PubMed2004

Melanocortin-4 receptor gene variant I103 is negatively associated with obesity.

Several rare mutations in the melanocortin-4 receptor gene (MC4R) predispose to obesity. For the most common missense variant V103I (rs2229616), however, the previously reported similar carrier frequencies in obese and nonobese individuals are in line with in vitro studies, which have not shown a functional implication of this variant. In the present study, we initially performed a transmission/disequilibrium test on 520 trios with obesity, and we observed a lower transmission rate of the I103 allele (P=.017), which was an unexpected finding. Therefore, we initiated two large case-control studies (N=2,334 and N=661) and combined the data with those from 12 published studies, for a total of 7,713 individuals. The resulting meta-analysis provides evidence for a negative association of the I103 allele with obesity (odds ratio 0.69; 95% confidence interval 0.50-0.96; P=.03), mainly comprising samples of European origin. Additional screening of four other ethnic groups showed comparable I103 carrier frequencies well below 10%. Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I. In our functional in vitro assays, the variant was indistinguishable from the wild-type allele, as was the result in previous studies. This report on an SNP/haplotype that is negatively associated with obesity expands the successful application of meta-analysis of modest effects in common diseases to a variant with a carrier frequency well below 10%. The respective protective effect against obesity implies that variation in the MC4R gene entails both loss and gain of function.

Animals↗
PubMed2004

Dopamine receptor gene polymorphisms in Parkinson's disease patients reporting "sleep attacks".

Genes encoding proteins involved in dopaminergic transmission are potential candidate genes for the induction of somnolence in Parkinson's disease (PD) because dopaminergic agents have been shown to be associated with sudden onset of sleep (SOS) in PD. We conducted an association study on dopamine D2, D3, and D4 receptor gene polymorphisms comparing 137 PD patients with SOS and 137 PD patients without SOS matched according to drug therapy, disease duration, sex, and age. Our results show a significant association between the dopamine D2 receptor gene polymorphism Taq IA and SOS in PD. No significant association between two other investigated polymorphisms and the phenomenon of "sleep attacks" in PD was observed.

Aged↗
PubMed2004

Ghrelin receptor gene: identification of several sequence variants in extremely obese children and adolescents, healthy normal-weight and underweight students, and children with short normal stature.

GH secretagogue receptor (GHSR, ghrelin receptor) is involved in regulation of body weight and GH secretion. We initially analyzed two single-nucleotide polymorphisms of the GHSR in up to 184 extremely obese children and adolescents and up to 184 healthy underweight students. The frequency of the 171T allele of rs495225 was higher in our obese samples (75.0%) than in the underweight individuals (70.2%; nominal P = 0.14). This trend could not be substantiated in an additional association study in 270 obese and 145 underweight and normal weight individuals and in a transmission disequilibrium test based on 387 obesity trios (transmission rate of 171T, 51.8%; nominal P = 0.53). Additionally, the coding region of GHSR was systematically screened, and seven sequence variants were identified in 93 obese, 96 normal weight, and 94 underweight individuals and 43 children with short normal stature (SNS). Five silent single-nucleotide polymorphisms showed similar genotype frequencies in the different weight groups and SNS children (all nominal P > 0.3). Two novel missense variants were detected only in one obese carrier and one SNS child, respectively. In conclusion, we did not obtain conclusive evidence for an involvement of the ghrelin receptor gene in body weight regulation or SNS in our study groups.

Adolescent↗
PubMed2003

Genome scan for body mass index and height in the Framingham Heart Study.

BACKGROUND: Body mass index (BMI) and adult height are moderately and highly heritable traits, respectively. To investigate the genetic background of these quantitative phenotypes, we performed a linkage genome scan in the extended pedigrees of the Framingham Heart Study. Two variance-components approaches (SOLAR and MERLIN-VC) and one regression method (MERLIN-REGRESS) were applied to the data. RESULTS: Evidence for linkage to BMI was found on chromosomes 16 and 6 with maximum LOD scores of 3.2 and 2.7, respectively. For height, all markers showing a LOD score greater than 1 in our analysis correspond to previously reported linkage regions, including chromosome 6q with a maximum LOD score of 2.45 and chromosomes 9, 12, 14, 18, and 22. Regarding the analysis, the three applied methods gave very similar results in this unselected sample with approximately normally distributed traits. CONCLUSION: Our analysis resulted in the successful identification of linked regions. In particular, we consider the regions on chromosomes 6 and 16 for BMI and the regions on chromosomes 6, 9, and 12 for stature interesting for fine mapping and candidate gene studies.

Adult↗
PubMed2003

Secular trends in body mass index measurements in preschool children from the City of Aachen, Germany.

UNLABELLED: On account of the recent increases in prevalence of childhood obesity in Western countries, the present study tried to verify a secular trend for increasing body mass index (BMI; kg/m(2)) in preschool children in Aachen, Germany. The total sample was based on weight and height data for all 99,500 children of German nationality before enrollment in school in the City of Aachen from 1968-1999. For each year, 10% of the boys and girls respectively, were randomly selected for the analyses. Quantile regression was used to examine the pattern and extent of change in BMI percentiles over this 31-year period. Anthropometric data of a total of 5081 boys and 4863 girls were subjected to quantile regression. While significant increases occurred for any given BMI percentile, the annual increase for both sexes was most prominent in the upper range. No change in body height was observed during the study period. CONCLUSION: preschool children have gained a higher body mass index during the last 30 years. The mechanisms underlying the secular trend towards increasing body mass index seemingly affect children in the upper weight range more than those in the lower range.

Body Height↗
PubMed2003

Lower serum leptin levels in female students of the nutritional sciences with eating disorders.

BACKGROUND: Evidence has accumulated that in both acutely ill and recovered patients with either anorexia or bulimia nervosa circulating leptin levels (LL) are lower than in controls matched for body mass index (BMI; kg/m(2)). It is unknown if these lower leptin levels represent a state or trait marker. AIM OF THE STUDY: We aimed to confirm the lowered leptin levels in eating disordered females and to identify underlying mechanisms. METHODS: We screened 181 female students of the nutritional sciences for eating disorders with the respective module of the M-Composite International Diagnostic Interview and the Cognitive Restraint scale of the Three Factor Eating Questionnaire. The physical assessment included determinations of BMI, body composition and LL. Each case fulfilling lifetime DSM-IV criteria for an eating disorder was BMI matched to two controls. We used a multivariate mixed regression model to evaluate if the observed difference in lg(10)-leptin level between cases and controls is actually due to the influence of restrained eating and/or previous weight loss after adjustment for BMI and percent body fat. RESULTS: In accordance with our hypothesis the 32 (17.7 %) cases had a lower serum lg(10)-leptin level than the 64 BMI matched controls (one-sided p < 0.001). We were not able to detect an influence of restrained eating or previous weight loss. CONCLUSIONS: We confirm that females with a lifetime history of an eating disorder have lower LL. We were not able to identify an underlying mechanism. Similar to most previous studies we found a high rate of eating disorders among female students of nutritional sciences.

Adult↗
PubMed2003

GSTP1 A1578G (Ile105Val) polymorphism in benzidine-exposed workers: an association with cytological grading of exfoliated urothelial cells.

A polymorphism at codon 105 (Ile/Val) in the GSTP1 gene has been associated with a higher risk for different cancer types. To assess the role of GSTP1 polymorphisms in the development of benzidine-related bladder cancer, GSTP1 AA, AG and GG genotypes were determined in occupationally benzidine-exposed Chinese workers without known disease and benzidine-exposed bladder cancer patients from the same cohort of the Shanghai area. An increased but not significant frequency of GSTP1 AG or GG carriers was observed in the occupationally exposed bladder cancer patient group [odds ratio (OR)=1.95, 95% confidence interval (CI) 0.70-5.46]. The odds ratios for the most important non-genetically determined risk factors for bladder cancer in male individuals were as follows: age (increase per year): OR 1.05, 95% CI 0.99-1.11; ever smoker: OR 1.31, 95% CI 0.47-3.69; duration of exposure (increase per year): OR 1.19, 95% CI 1.10-1.29; and high exposure: OR 4.50, 95% CI 0.70-5.46. Significant differences were found between all benzidine-exposed workers without known disease with modified exfoliated urothelial cells (grade II and higher) and all workers without known disease with at most minor changes (less than grade II) according to Papanicolaou (OR 1.90, 95% CI 1.13-3.20). These findings show for the first time an association between the GSTP1 AG or GG genotype and higher cytological gradings of exfoliated urothelial cells from formerly benzidine-exposed workers.

Aged↗