| 1. |
- Turcot, Valerie, et al.
(författare)
-
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
|
|
| 2. |
- Justice, Anne E., et al.
(författare)
-
Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
-
Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
|
|
| 3. |
- Mattsson, Andreas, et al.
(författare)
-
Infrared spectroscopy study of adsorption and photodecomposition of formic acid on reduced and defective rutile TiO2 (110) surfaces
- 2014
-
Ingår i: Journal of Vacuum Science & Technology. A. Vacuum, Surfaces, and Films. - : American Vacuum Society. - 0734-2101 .- 1520-8559. ; 32:6
-
Tidskriftsartikel (refereegranskat)abstract
- Adsorption and photodecomposition of formic acid on rutile TiO2 (110) have been investigated with infrared reflection–absorption spectroscopy (IRRAS) employing p- and s-polarized light along the [001] and [ 11⎯⎯0 ] crystal directions. The single crystal surfaces were prepared either by sputtering and annealing in ultrahigh vacuum (UHV) to obtain a reduced surface (r-TiO2), or by sputtering without annealing to create a rough, highly defective surface (sp-TiO2). Results are compared with corresponding measurements on rutile nanocrystals performed in synthetic air. IRRAS spectra obtained on r-TiO2 and rutile nanocrystals are very similar, and show that in both cases formic acid dissociates and is predominately adsorbed as a bridging bidentate formate species, and that the formate adsorption structure on the nanocrystals is dominated by interactions with majority (110) surfaces. In contrast, the IRRAS spectra on sp-TiO2 are different, with only minor spectral features associated with (110) surfaces and lost azimuthal symmetry, both of which imply changed adsorption geometry due to bonding to low-coordinated Ti atoms with lower valences. The UV-induced rate of formate photodecomposition is about 30 times higher on rutile nanocrystals in synthetic air compared with sp-TiO2 under UHV conditions, and even larger than on r-TiO2. These differences are explained by the lack of oxygen and limited hydroxyl coverage under UHV conditions. The difference in reactivity between the r-TiO2 and sp-TiO2 surfaces is attributed to a high concentration of strongly bonded bridging bidentate formate species on the (110) surface, which lowers its reactivity. The results point to a pressure gap where the availability of molecular oxygen and the hydroxyl concentration limit the photoreactivity in UHV leading to an almost 20-fold decrease of the formate degradation rate in UHV. In contrast, the structure represented by the single crystal (110) surface is shown to capture the essential structural properties, which dictates the formic acid adsorption and adsorption structure of rutile nanocrystals.
|
|
