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  • 1.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chrousos, George P.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Genome wide analysis reveals association of a FTO gene variant with epigenetic changes2012In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 99, no 3, p. 132-137Article in journal (Refereed)
    Abstract [en]

    Variants of the FTO gene show strong association with obesity, but the mechanisms behind this association remain unclear. We determined the genome wide DNA methylation profile in blood from 47 female preadolescents. We identified sites associated with the genes KARS, TERF2IP, DEXI, MSI1,STON1 and BCAS3 that had a significant differential methylation level in the carriers of the FTO risk allele (rs9939609). In addition, we identified 20 differentially methylated sites associated with obesity. Our findings suggest that the effect of the FTO obesity risk allele may be mediated through epigenetic changes. Further, these sites might prove to be valuable biomarkers for the understanding of obesity and its comorbidites.

  • 2.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rönnemaa, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    Interdisciplinary Obesity Center, Kantonsspital St. Gallen.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 6, p. 1159.e1-1159.e5Article in journal (Refereed)
    Abstract [en]

    Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.

  • 3.
    Jacobsson, J. A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kapa, I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Danielsson, P
    Svensson, V
    Ridderstråle, M
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Marcus, C
    Fredriksson, R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents.2008In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 32, no 11, p. 1730-1735Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    The global prevalence of obesity and overweight is increasing rapidly among adults as well as among children and adolescents. Recent genome-wide association studies have provided strong support for association between variants in the FTO gene and obesity. We sequenced regions of the FTO gene to identify novel variants that are associated with obesity and related metabolic traits.

    RESULTS

    We screened exons 3 and 4 including exon-intron boundaries in FTO in 48 obese children and adolescents and identified three novel single nucleotide polymorphism in the fourth intronic region, (c.896+37A>G, c.896+117C>G and c.896+223A>G). We further genotyped c.896+223A>G in 962 subjects, 450 well-characterized obese children and adolescents and 512 adolescents with normal weight. Evidence for differences in genotype frequencies were not detected for the c.896+223A>G variant between extremely obese children and adolescents and normal weight adolescents (P=0.406, OR=1.154 (0.768-1.736)). Obese subjects with the GG genotype, however, had 30% increased fasting serum insulin levels (P=0.017) and increased degree of insulin resistance (P=0.025). There were in addition no differences in body mass index (BMI) or BMI standard deviation score (SDS) levels among the obese subjects according to genotype and the associations with insulin levels and insulin resistance remained significant when adjusting for BMI SDS.

    CONCLUSION

    These findings suggest that this novel variant in FTO is affecting metabolic phenotypes such as insulin resistance, which are not mediated through differences in BMI levels.

  • 4.
    Jacobsson, Josefin A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Danielsson, Pernilla
    Svensson, Victoria
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Marcus, Claude
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes.2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 368, no 3, p. 476-482Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P=0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.

  • 5.
    Jacobsson, Josefin A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schioth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Rorbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The impact of intronic single nucleotide polymorphisms and ethnic diversity for studies on the obesity gene FTO2012In: Obesity Reviews, ISSN 1467-7881, E-ISSN 1467-789X, Vol. 13, no 12, p. 1096-1109Article, review/survey (Refereed)
    Abstract [en]

    In 2007, the first common genetic variants were identified, which undoubtedly affect our susceptibility to obesity. These variants are located in the fat mass and obesity-associated gene FTO. Since then, over 50 loci for common obesity have been identified. As the research on these loci is still at an early stage, there is a great need to review, for clarification purposes, the current research on FTO, as this is likely to influence future studies. Based on the current knowledge, FTO seems to be directly involved in the regulation of energy intake, but there is an urgent need for the identification of regulatory polymorphisms. Thus, herein, we discuss current knowledge and highlight putative functional regions in FTO based on published data and computer-based analysis.

  • 6.
    Jacobsson, Josefin A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hedberg, Lilia A.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 5, p. e20158-Article in journal (Refereed)
    Abstract [en]

    Background

     The rs9939609 single-nucleotide polymorphism (SNP) in the fat mass and obesity (FTO) gene has previously been associated with higher BMI levels in children and young adults. In contrast, this association was not found in elderly men. BMI is a measure of overweight in relation to the individuals' height, but offers no insight into the regional body fat composition or distribution.

    Objective

    To examine whether the FTO gene is associated with overweight and body composition-related phenotypes rather than BMI, we measured waist circumference, total fat mass, trunk fat mass, leg fat mass, visceral and subcutaneous adipose tissue, and daily energy intake in 985 humans (493 women) at the age of 70 years. In total, 733 SNPs located in the FTO gene were genotyped in order to examine whether rs9939609 alone or the other SNPs, or their combinations, are linked to obesity-related measures in elderly humans.

    Design

    Cross-sectional analysis of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort.

    Results

     Neither a single SNP, such as rs9939609, nor a SNP combination was significantly linked to overweight, body composition-related measures, or daily energy intake in elderly humans. Of note, these observations hold both among men and women.

    Conclusions

    Due to the diversity of measurements included in the study, our findings strengthen the view that the effect of FTO on body composition appears to be less profound in later life compared to younger ages and that this is seemingly independent of gender.

  • 7.
    Jacobsson, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Moschonis, G
    Koumpitski, A
    Chrousos, G P
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marcus, C
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Genetic variants near the MGAT1 gene are associated with body weight, BMI and fatty acid metabolism among adults and children2012In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 36, no 1, p. 119-129Article in journal (Refereed)
    Abstract [en]

    Objective: Recently a genome-wide association analysis from five European populations identified a polymorphism located downstream of the mannosyl-(α-1,3)-glycoprotein-β-1,2-N-acetylglucosaminyltransferase (MGAT1) gene that was associated with body-weight. In the present study, associations between MGAT1 variants combined with obesity and insulin measurements were investigated in three cohorts. Levels of fatty acids and estimated measures of Δ desaturases were also investigated among adult men.

    Design: Six polymorphisms downstream of MGAT1 were genotyped in a cross-sectional cohort of 1152 Swedish men. Three polymorphisms were further analyzed in a case-control study of 1076 Swedish children and in a cross-sectional study of 2249 Greek children.

    Results: Three polymorphisms, rs12186500 (odds ratio (OR): 1.892, 95% confidence interval (CI): 1.237-2.895, P=0.003), rs1021001 (OR: 2.102, 95% CI: 1.280-3.455, P=0.003) and rs4285184 (OR: 1.587, 95% CI: 1.024-2.459, P=0.038) were associated with a higher prevalence of obesity among the adult men and a trend for obesity was observed for rs4285184 among the Swedish (OR: 1.205, 95% CI: 0.987-1.471, P=0.067) and Greek children (OR: 1.192, 95%CI: 0.978-1.454, P=0.081). Association with body weight was observed for rs12186500 (P=0.017) and rs4285184 (P=0.024) among the men. The rs1021001 and rs4285184 were also associated with body mass index (BMI) in the two Swedish cohorts and similar trends were observed among the Greek children. The combined effect size for rs1021001 and rs4285184 on BMI z-score from a meta-analysis was 0.233 (95% CI:0.093-0.373, P=0.001) and 0.147 (95% CI:0.057-0.236, P=0.001), respectively. We further observed associations between the genetic variants and fatty acids (P<0.039) and estimated measures of Δ desaturases (P<0.040), as well as interactions for rs12186500 (P<0.019) with an effect on BMI. No association was found with homeostatic model assessment-insulin resistance in any cohort but increased insulin levels, insulin response and decreased insulin sensitivity were observed among the children (P<0.038).

    Conclusion: Genetic variants downstream MGAT1 seem to influence susceptibility to obesity. Moreover, these genetic variants affect the levels of serum unsaturated fatty acids and Δ desaturase indices, variables previously shown to correlate with obesity.

  • 8.
    Kalnina, Ineta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zaharenko, Linda
    Vaivade, Iveta
    Rovite, Vita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nikitina-Zake, Liene
    Peculis, Raitis
    Fridmanis, Davids
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Geldnere, Kristine
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pirags, Valdis
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes2013In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 527, no 2, p. 462-468Article in journal (Refereed)
    Abstract [en]

    Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, but have also been linked with type 2 diabetes (T2D). Our aim was to investigate the contribution of these variants to risk of T2D in a population in Latvia. Four single nucleotide polymorphisms (SNP) in the first and fourth intronic regions of FTO and one close to TMEM18 were genotyped in 987 patients with T2D and 1080 controls selected from the Latvian Genome Data Base (LGDB). We confirmed association of SNPs in the first intron (rs11642015, rs62048402 and rs9939609) of FTO and rs7561317 representing the TMEM18 locus with T2D. Association between SNP in FTO and T2D remained significant after correction for body mass index (BMI). The rs57103849 located in the fourth intron of FTO and rs7561317 in TMEM18 showed BMI independent association with younger age at diagnosis of T2D. Our results add to the evidence that BMI related variants in and near FTO and TMEM18 may increase the risk for T2D not only through secondary effects of obesity. The influence of variants in the fourth intron of the FTO gene on development of T2D may be mediated by mechanisms other than those manifested by SNPs in the first intron of the same gene.

  • 9.
    Olszewski, Pawel K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rozman, Jan
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rathkolb, Birgit
    Strömberg, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Hans, Wolfgang
    Klockars, Anica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Becker, Lore
    Hoelter, Sabine M.
    Elvert, Ralf
    Ehrhardt, Nicole
    Gailus-Durner, Valerie
    Fuchs, Helmut
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wolf, Eckhard
    Klopstock, Thomas
    Wurst, Wolfgang
    Levine, Allen S.
    Marcus, Claude
    de Angelis, Martin Hrabe
    Klingenspor, Martin
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kilimann, Manfred W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans2012In: PLoS Genetics, ISSN 1553-7390, Vol. 8, no 3, p. e1002568-Article in journal (Refereed)
    Abstract [en]

    Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/- mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity.

  • 10.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Chavan, Rohit A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sikder, Md Abu Noman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Allzén, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chrousos, George P.
    Manios, Yannis
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association of TMEM18 variants with BMI and waist circumference in children and correlation of mRNA expression in the PFC with body weight in rats2012In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 2, p. 192-197Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have shown a strong association of single-nucleotide polymorphisms (SNPs) in the near vicinity of the TMEM18 gene. The effects of the TMEM18-associated variants are more readily observed in children. TMEM18 encodes a 3TM protein, which locates to the nuclear membrane. The functional context of TMEM18 and the effects of its associated variants are as of yet undetermined. To further explore the effects of near-TMEM18 variants, we have genotyped two TMEM18-associated SNPs, rs6548238 and rs4854344, in a cohort of 2352 Greek children (Healthy Growth Study). Included in this study are data on anthropomorphic traits body weight, BMI z-score and waist circumference. Also included are dietary energy and macronutrient intake as measured via 24-h recall interviews. Major alleles of rs6548238 and rs4854344 were significantly associated with an increased risk of obesity (odds ratio=1.489 (1.161-1.910) and 1.494 (1.165-1.917), respectively), and positively correlated to body weight (P=0.017, P=0.010) and waist circumference (P=0.003, P=0.003). An association to energy and macronutrient intake was not observed in this cohort. We also correlated food intake and body weight in a food choice model in rats to Tmem18 expression in central regions involved in feeding behavior. We observed a strong positive correlation between TMEM18 expression and body weight in the prefrontal cortex (PFC) (r=0.5694, P=0.0003) indicating a potential role for TMEM18 in higher functions related to feeding involving the PFC.

  • 11.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Ek, Anna E.
    Chrousos, George P.
    Marcus, Claude
    Manios, Yannis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The MAP2K5-linked SNP rs2241423 is associated with BMI and obesity in two cohorts of Swedish and Greek children2012In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, p. 36-Article in journal (Refereed)
    Abstract [en]

    Background

    Recent genome-wide association studies have identified a single nucleotide polymorphism within the last intron of MAP2K5 associated with a higher body mass index (BMI) in adults. MAP2K5 is a component of the MAPK-family intracellular signaling pathways, responding to extracellular growth factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). In this study, we examined the association of this variant in two cohorts of children from Sweden and Greece.

    Methods

    We examine the association of rs2241423 to BMI in a cohort of 474 Swedish children admitted for treatment of childhood obesity and 519 children matched for gender, ethnicity and socioeconomic background from the Stockholm area, as well as a cross-sectional cohort of 2308 Greek school children (Healthy Growth Study). Children were genotyped using a predesigned TaqMan polymorphism assay. Logistic regression was used to test for an association of rs2241423 to obesity in the cohort of Swedish children. Linear regression was used to test for an association of rs2241423 to BMI z-score and phenotypic measurements of body adiposity in the cohort of Greek children. Models were adjusted for age and gender. In the cohort of Greek children the model was also adjusted for stage of pubertal development.

    Results

    The minor allele of rs2241423, allele A, was associated with a protective effect against obesity in the cohort of Swedish children (p = 0.029, OR = 0.79 (95% CI: 0.64-0.98)), and with a lower BMI z-score in the cohort of Greek children (p = 0.028, beta = -0.092). No association to phenotypic measurements of body fat distribution could be observed in our study.

    Conclusions

    rs2241423 was associated with BMI and obesity in two independent European cohorts suggesting a role for MAP2K5 in early weight regulation.

  • 12.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Moschonis, George
    Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
    Manios, Yannis
    Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
    Marcus, Claude
    Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Division of Pediatrics, National Childhood Obesity Centre, Stockholm, Sweden.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ultra-deep targeted re-sequencing of TMEM18 in two cohorts of European children detects new genetic variants associated with obesity2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
  • 13.
    Sällman Almén, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kalnina, I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, G
    Juhlin, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bringeland, Nathalie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hedberg, Lidwig A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ignatovica, V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chrousos, G P
    Manios, Y
    Klovins, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Marcus, C
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Determination of the obesity-associated gene variants within the entire FTO gene by ultra-deep targeted sequencing in obese and lean children.2013In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 37, no 3, p. 424-431Article in journal (Refereed)
    Abstract [en]

    Background:The Fat mass and obesity-associated gene (FTO) was the first gene reliably associated with body mass index in genome-wide association studies on a population level. At present, the genetic variations within the FTO gene are still the common variants that have the largest influence on body mass index.Methods:In the current study, we amplified the entire FTO gene, in total 412 Kbp, in over 200 long-range PCR fragments from each individual, from 524 severely obese and 527 lean Swedish children, and sequenced the products as two DNA pools using massive parallel sequencing (SOLiD).Results:The sequencing achieved very high coverage (median 18 000 reads) and we detected and estimated allele frequencies for 705 single nucleotide polymorphisms (SNPs) (19 novel) and 40 indels (24 novel) using a sophisticated statistical approach to remove false-positive SNPs. We identified 19 obesity-associated SNPs within intron one of the FTO gene, and validated our findings with genotyping. Ten of the validated obesity-associated SNPs have a stronger obesity association (P<0.007) than the commonly studied rs9939609 SNP (P<0.012).Conclusions:This study provides a comprehensive obesity-associated variation map of FTO, identifies novel lead SNPs and evaluates putative causative variants. We conclude that intron one is the only region within the FTO gene associated with obesity, and finally, we establish next generation sequencing of pooled DNA as a powerful method to investigate genetic association with complex diseases and traits.

  • 14.
    Västermark, Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Polymorphisms in sh2b1 and spns1 loci are associated with triglyceride levels in a healthy population in northern Sweden2012In: Journal of Genetics, ISSN 0022-1333, E-ISSN 0973-7731, Vol. 91, no 2, p. 237-240Article in journal (Refereed)
1 - 14 of 14
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