https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:50431 Wed 28 Aug 2024 15:49:50 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:45256 1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.]]> Wed 26 Oct 2022 20:06:39 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:43392 Wed 22 Mar 2023 15:32:42 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:52463 Wed 11 Oct 2023 15:07:44 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:50411 Tue 25 Jul 2023 17:30:33 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:41899 PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.]]> Tue 16 Aug 2022 08:27:58 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:44342 Tue 11 Oct 2022 19:28:24 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:48599 Tue 04 Apr 2023 19:22:25 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:46138 Tue 04 Apr 2023 18:59:19 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:45201 P = 3.96 x 10^-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.]]> Thu 27 Oct 2022 15:06:39 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:46603 Fri 25 Nov 2022 16:41:41 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:53055 Fri 17 Nov 2023 11:47:02 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:41815 Fri 12 Aug 2022 12:45:25 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:46943 METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.]]> Fri 09 Dec 2022 14:01:32 AEDT ]]>