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- Tabassum, R, et al.
(författare)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 4. |
- Porcu, E, et al.
(författare)
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Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3300-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
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| 5. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 7. |
- Bos, I., et al.
(författare)
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Amyloid-beta, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data
- 2018
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether amyloid-beta (A beta) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had A beta status and neuropsychological data available. Linear mixed models were used to assess the associations of Ali and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without A beta pathology (A beta- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the A beta- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Ao and cognition in cognitively normal individuals. The Af3- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.
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| 8. |
- Surakka, Ida, et al.
(författare)
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The impact of low-frequency and rare variants on lipid levels.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:6, s. 589-597
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Tidskriftsartikel (refereegranskat)abstract
- Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
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| 10. |
- Wallin, Anders, 1950, et al.
(författare)
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Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease
- 2018
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 62:3, s. 1417-1441
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Forskningsöversikt (refereegranskat)abstract
- Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.
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