<i>CPT1A</i>
            Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders

Skotte, Line; Koch, Anders; Yakimov, Victor; Zhou, Sirui; Søborg, Bolette; Andersson, Mikael; Michelsen, Sascha Wilk; Navne, Johan E.; Mistry, Jacqueline M.; Dion, Patrick A.; Pedersen, Michael Lynge; Børresen, Malene Landbo; Rouleau, Guy A.; Geller, Frank; Melbye, Mads; Feenstra, Bjarke

doi:10.1161/circgenetics.116.001618

Cited by 32 publications

(34 citation statements)

References 34 publications

(47 reference statements)

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“…The Yup'ik individuals were 14 years or older, and were recruited by the Center for Alaska Native Health Research from 11 Southwest Alaska communities. The Greenlanders were 16 years or older, and participant samples were collected as a population-based sample from seven towns [45]. There was an overlap of 41 individuals between stage 1 and stage 2 Greenlandic cohorts, these individuals were assigned to the stage 1 cohort.…”

Section: Stage 2 Study Populationsmentioning

confidence: 99%

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders

et al. 2020

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The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10 -8 ), corresponding to 0.64 kg/m 2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The

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Section: Stage 2 Study Populationsmentioning

confidence: 99%

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders

et al. 2020

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“…These discoveries include type 2 diabetes susceptibility variants in ABCC8 identified in Pima Indians , and in TBC1D4 identified in Greenlanders , as well as in SLC16A11 and HNF1A identified in the admixed Mexican population , where also a protective type 2 diabetes variant has been identified in IGF2 . Moreover, variants associated with lower lipid levels in APOC3 and DSCAML1 have been identified in an isolated Greek population , variants associated with levels of fatty acids in ACSL6 and CPT1A have been identified in Greenlanders , as well as variants associated with obesity in CREBRF and ADCY3 in Samoans and Greenlanders, respectively , and increased fasting insulin in AKT2 identified in Finns .…”

Section: Genetic Association Studies Of Metabolic Traits In Isolated mentioning

confidence: 97%

“…The strongest signature of positive selection reported in Greenlanders and Siberians maps to a region on chromosome 11 . In this region, selection signals in Greenlanders have been mapped to a cluster of fatty acid desaturase genes ( FADS1, FADS2 and FADS3 ) , and CPT1A . In CPT1A, the positive selection signal seems to be driven by the Pro479Leu missense variant (rs80356779, c.1436C>T) .…”

Section: Genetic Association Studies Of Metabolic Traits In Isolated mentioning

confidence: 99%

“…In this region, selection signals in Greenlanders have been mapped to a cluster of fatty acid desaturase genes ( FADS1, FADS2 and FADS3 ) , and CPT1A . In CPT1A, the positive selection signal seems to be driven by the Pro479Leu missense variant (rs80356779, c.1436C>T) . The T‐allele (479Leu) of this variant is fixed in the ancestral Inuit population, along with the rs174570 variant mapping to FADS2, even though there is around 7 Mb between these two variants .…”

Section: Genetic Association Studies Of Metabolic Traits In Isolated mentioning

confidence: 99%

“…The CPT1A Pro479Leu variant, linked to the selection signal, was first observed in a CPT1A‐deficient patient , and has subsequently been linked to altered metabolic phenotypes in Greenlanders and Yup'ik Eskimoes . More recently, the variant has been shown to be associated with altered patterns of fatty acids in erythrocyte membranes and serum, as well as reduced body size among Greenlanders .…”

Section: Genetic Association Studies Of Metabolic Traits In Isolated mentioning

confidence: 99%

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Genetics of metabolic traits in Greenlanders: lessons from an isolated population

Andersen

Hansen

2018

J Intern Med

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In this review, we describe the extraordinary population of Greenland, which differs from large outbred populations of Europe and Asia, both in terms of population history and living conditions. Many years in isolation, small population size and an extreme environment have shaped the genetic composition of the Greenlandic population. The unique genetic background combined with the transition from a traditional Inuit lifestyle and diet, to a more Westernized lifestyle, has led to an increase in the prevalence of metabolic conditions like obesity, where the prevalence from 1993 to 2010 has increased from 16.4% to 19.4% among men, and from 13.0% to 25.4% among women, type 2 diabetes and cardiovascular diseases. The genetic susceptibility to metabolic conditions has been explored in Greenlanders, as well as other isolated populations, taking advantage of population-genetic properties of these populations. During the last 10 years, these studies have provided examples of loci showing evidence of positive selection, due to adaption to Arctic climate and Inuit diet, including TBC1D4 and FADS/CPT1A, and have facilitated the discovery of several loci associated with metabolic phenotypes. Most recently, the c.2433-1G>A loss-of-function variant in ADCY3 associated with obesity and type 2 diabetes was described. This locus has provided novel biological insights, as it has been shown that reduced ADCY3 function causes obesity through disrupted function in primary cilia. Future studies of isolated populations will likely provide further genetic as well as biological insights.

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Sex differences in adipose development in a hunter‐gatherer population

Kramer

Achenbach

Hackman

2021

American J Hum Biol

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Objective Humans are unusually sexually dimorphic in body composition, with adult females having on average nearly twice the fat mass as males. The development of adipose sex differences has been well characterized for children growing up in food‐abundant environments, with less known about cross‐cultural variation, particularly in populations without exposure to market foods, mechanized technologies, schooling, vaccination, or other medical interventions. Methods To add to the existing cross‐cultural data, we fit multiple growth curves to body composition and anthropometric data to describe adipose development for the Savanna Pumé, South American hunter‐gatherers. Results (1) Little evidence is found for an adiposity ‘rebound’ at the end of early childhood among either Savanna Pumé girls or boys. (2) Rather, fat deposition fluctuates during childhood, from age ~4 to ~9 years, with no appreciable accumulation until the onset of puberty, a pattern also observed among Congo Baka hunter‐gatherers. (3) Body fat fluctuations are more pronounced for girls than boys. (4) The age of peak skeletal, weight, and adipose gains are staggered to a much greater extent among the Savanna Pumé compared to the National Health and Nutrition Examination Survey (NHANES III) reference, suggesting this is an important developmental strategy in lean populations. Conclusion Documenting growth patterns under diverse preindustrial energetic conditions provides an important baseline for understanding sex differences in body fat emerging today under food abundance.

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CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders

Cited by 32 publications

References 34 publications

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders

Genetics of metabolic traits in Greenlanders: lessons from an isolated population

Sex differences in adipose development in a hunter‐gatherer population

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