Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

Þorleifsson, Guðmar; Walters, G. Bragi; Guðbjartsson, Daníel F.; Steinthórsdóttir, Valgerður; Sulem, Patrick; Helgadóttir, Anna; Styrkársdóttir, Unnur; Grétarsdóttir, Sólveig; Thorlacius, Steinunn; Jónsdóttir, Ingileif; Jónsdóttir, Þorbjörg; Ólafsdóttir, Elínborg J; Olafsdottir, Gudridur H; Jónsson, Þorvaldur; Jónsson, Frosti; Borch‐Johnsen, Knut; Hansen, Torben; Andersen, Gitte; Jørgensen, Torben; Lauritzen, Torsten; Aben, Katja K.H.; Verbeek, A.L.M.; Roeleveld, Nel; Kampman, Ellen; Yanek, Lisa R.; Becker, Lewis C.; Tryggvadóttír, Laufey; Rafnar, Thorunn; Becker, Diane M.; Gulcher, Jeffrey R.; Kiemeney, Lambertus A.; Pedersen, Oluf; Kong, Augustine; Þorsteinsdóttir, Unnur; Stefánsson, Kári

doi:10.1038/ng.274

Cited by 1,234 publications

(1,197 citation statements)

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“…(2010), who failed to find a significant effect of a KCTD15 polymorphism previously associated with obesity in AN patients; as well as with several GWAS, which have not identified any KCTD15 SNP related to AN risk (Boraska et al., 2014; Hinney et al., 2017; Wang et al., 2011). In this regard, several loci in or near KCTD15 have repeatedly been associated with obesity in a number of GWAS and replication studies (Mei et al., 2012; Paternoster et al., 2011; Thorleifsson et al., 2009; Willer et al., 2009). The cerebral location of the gene indicates that its association with weight increase would likely be based on changes in feeding behavior.…”

Section: Discussionmentioning

confidence: 99%

Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa

et al. 2017

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Introduction TFAP2B and KCTD15 are obesity‐related genes that interact to regulate feeding behavior. We hypothesize that variability in these loci, isolated or in combination, could also be related to the risk of eating disorders (ED) and/or associated psychological traits.MethodsWe screened 425 participants (169 ED patients, 75 obese subjects, and 181 controls) for 10 clinically relevant and tag single‐nucleotide polymorphisms (SNPs) in KCTD15 and TFAP2B by the Sequenom MassARRAY platform and direct sequencing. Psychometric evaluation was performed with EDI‐2 and SCL‐90R inventories.ResultsThe KCTD15 rs287103 T variant allele was associated with increased risk of bulimia nervosa (BN) (OR = 4.34 [1.47–29.52]; p = .003) and with scores of psychopathological scales of these patients. Haplotype *6 in KCTD15 was more frequent in controls (OR = 0.40 [0.20–0.80], p = .009 for anorexia nervosa), while haplotype *4 in TFAP2B affected all three scales of the SCL‐90R inventory in BN patients (p ≤ .01). Epistasis analyses revealed relevant interactions with body mass index of BN patients (p < .001). Genetic profiles in obese patients did not significantly differ from those found in ED patients.ConclusionsThis is the first study that evaluates the combined role of TFAP2B and KCTD15 genes in ED. Our preliminary findings suggest that the interaction of genetic variability in these loci could influence the risk for ED and/or anthropometric and psychological parameters.

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Section: Discussionmentioning

confidence: 99%

Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa

et al. 2017

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“…Among those, SH2B1 encodes a Src homology adaptor protein involved in leptin and insulin signaling. 25,26 Common variants near this locus are associated with BMI, serum leptin, and body fat in genome-wide association studies (GWASs), [27][28][29][30] while rare dominant mutations have been reported to cause obesity, social isolation, aggressive behavior, and speech and language delay. 31 None of the CNV-contained genes have been associated with ASD or HC defects.…”

Section: Introductionmentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

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et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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“…SNP rs11926347, in an intron of ABCC5 (OMIM 60521), and SNP rs6795506, near the 5' end of AHSG (OMIM 138680), had extremely small p-values (Table 8). Among the other nine genes, ADIPOQ (OMIM 605441, 612556) has been widely reported to be associated with obesity and diabetes [21-24]; FNDC3B (OMIM 611909) is involved in positive regulation of adipogenesis [25]; and DGKG (OMIM 601854) and AHSG (OMIM 138680) have been reported to be associated with obesity-related metabolic traits [26,27]. The remaining genes have no reported relation to obesity-related metabolic traits based on our literature review.…”

Section: Resultsmentioning

confidence: 99%

Principal-component-based multivariate regression for genetic association studies of metabolic syndrome components

et al. 2010

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BackgroundQuantitative traits often underlie risk for complex diseases. For example, weight and body mass index (BMI) underlie the human abdominal obesity-metabolic syndrome. Many attempts have been made to identify quantitative trait loci (QTL) over the past decade, including association studies. However, a single QTL is often capable of affecting multiple traits, a quality known as gene pleiotropy. Gene pleiotropy may therefore cause a loss of power in association studies focused only on a single trait, whether based on single or multiple markers.ResultsWe propose using principal-component-based multivariate regression (PCBMR) to test for gene pleiotropy with comprehensive evaluation. This method generates one or more independent canonical variables based on the principal components of original traits and conducts a multivariate regression to test for association with these new variables. Systematic simulation studies have shown that PCBMR has great power. PCBMR-based pleiotropic association studies of abdominal obesity-metabolic syndrome and its possible linkage to chromosomal band 3q27 identified 11 susceptibility genes with significant associations. Whereas some of these genes had been previously reported to be associated with metabolic traits, others had never been identified as metabolism-associated genes.ConclusionsPCBMR is a computationally efficient and powerful test for gene pleiotropy. Application of PCBMR to abdominal obesity-metabolic syndrome indicated the existence of gene pleiotropy affecting this syndrome.

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Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

Cited by 1,234 publications

References 35 publications

Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa

Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Principal-component-based multivariate regression for genetic association studies of metabolic syndrome components

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