| 1. |
- Hicks, Andrew A., et al.
(författare)
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Genetic determinants of circulating sphingolipid concentrations in European populations
- 2009
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:10, s. e1000672-
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Tidskriftsartikel (refereegranskat)abstract
- Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic β-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08×10−66. The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1–3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10−4 or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases.
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| 2. |
- Pattaro, Cristian, et al.
(författare)
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The Cooperative Health Research in South Tyrol (CHRIS) study : rationale, objectives, and preliminary results
- 2015
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The Cooperative Health Research In South Tyrol (CHRIS) study is a population-based study with a longitudinal lookout to investigate the genetic and molecular basis of age-related common chronic conditions and their interaction with life style and environment in the general population. All adults of the middle and upper Vinschgau/Val Venosta are invited, while 10,000 participants are anticipated by mid-2017. Family participation is encouraged for complete pedigree reconstruction and disease inheritance mapping. After a pilot study on the compliance with a paperless assessment mode, computer-assisted interviews have been implemented to screen for conditions of the cardiovascular, endocrine, metabolic, genitourinary, nervous, behavioral, and cognitive system. Fat intake, cardiac health, and tremor are assessed instrumentally. Nutrient intake, physical activity, and life-course smoking are measured semi-quantitatively. Participants are phenotyped for 73 blood and urine parameters and 60 aliquots per participant are biobanked (cryo-preserved urine, DNA, and whole and fractionated blood). Through liquid-chromatography mass-spectrometry analysis, metabolite profiling of the mitochondrial function is assessed. Samples are genotyped on 1 million variants with the Illumina HumanOmniExpressExome array and the first data release including 4570 fully phenotyped and genotyped samples is now available for analysis. Participants' follow-up is foreseen 6 years after the first visit. The target population is characterized by long-term social stability and homogeneous environment which should both favor the identification of enriched genetic variants. The CHRIS cohort is a valuable resource to assess the contribution of genomics, metabolomics, and environmental factors to human health and disease. It is awaited that this will result in the identification of novel molecular targets for disease prevention and treatment.
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| 3. |
- Pichler, Irene, et al.
(författare)
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Fine-Mapping of Restless Legs Locus 4 (RLS4) Identifies a Haplotype over the SPATS2L and KCTD18 Genes
- 2013
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Ingår i: Journal of Molecular Neuroscience. - : Springer Science and Business Media LLC. - 0895-8696 .- 1559-1166. ; 49:3, s. 600-605
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Tidskriftsartikel (refereegranskat)abstract
- Restless legs syndrome (RLS) is a sleep-related movement disorder that affects up to 15 % of the population. Linkage studies have identified several genomic loci in single families (12q, 14q, 9p, 2q, 20p and 16p, respectively). However, confirmation of these loci has not always been achieved, and causative mutations have not yet been identified. The locus on chromosome 2q33 (RLS4) was identified in two South Tyrolean families who shared a haplotype of microsatellite marker alleles across an 8.2-cM region. To pinpoint the gene localisation within RLS4, additional families from the same geographic region were evaluated, and linkage was replicated in one family. Within the candidate region, we initially found a haplotype of 23 single nucleotide polymorphism markers spanning 131.6 Kb shared by all affected members of the three linked families. Using a next generation sequencing approach, we further restricted the shared candidate region to 46.9 Kb over the potassium channel-related gene KCTD18 and exons 10-13 of SPATS2L.
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