| 1. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 2. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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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.
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| 3. |
- Tøllefsen, Ingvild Maria, et al.
(författare)
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Are suicide deaths under-reported? Nationwide re-evaluations of 1800 deaths in Scandinavia.
- 2015
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 5:11
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Valid mortality statistics are important for healthcare planning and research. Suicides and accidents often present a challenge in the classification of the manner of death. The aim of this study was to analyse the reliability of the national suicide statistics by comparing the classification of suicide in the Scandinavian cause of death registers with a reclassification by 8 persons with different medical expertise (psychiatry, forensic pathology and public health) from each of the 3 Scandinavian countries.METHODS: The cause of death registers in Norway, Sweden and Denmark retrieved available information on a sample of 600 deaths in 2008 from each country. 200 were classified in the registers as suicides, 200 as accidents or undetermined and 200 as natural deaths. The reclassification comprised an assessment of the manner and cause of death as well as the level of certainty.RESULTS: In total, 81%, 88% and 90% of deaths registered as suicide in the official mortality statistics were confirmed by experts using the Swedish, Norwegian and Danish data sets, respectively. About 3% of deaths classified as accidents or natural deaths in the cause of death registers were reclassified as suicides. However, after a second reclassification based on additional information, 9% of the natural deaths and accidents were reclassified as suicides in the Norwegian data set, and 21% of the undetermined deaths were reclassified as suicides in the Swedish data set. In total, the levels of certainty of the experts were 87% of suicides in the Norwegian data set, 77% in the Swedish data set and 92% in Danish data set; the uncertainty was highest in poisoning suicides.CONCLUSIONS: A high percentage of reported suicides were confirmed as being suicides. Few accidents and natural deaths were reclassified as suicides. Hence, reclassification did not increase the overall official suicide statistics of the 3 Scandinavian countries.
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