Muller-Nuraysid, M. | Search bioRxiv

bioRxiv2019

Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease

BackgroundAdvanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of the preceding early stages of the diseases. MethodsTo identify genetic factors for early AMD, we conducted a genome-wide association meta-analysis with 14,034 early AMD cases and 91,214 controls from 11 sources of data including data from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank (UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and by using an automated machine learning approach for >170,000 images from UKBB. We searched for significant genetic loci in a genome-wide association screen (P<5x10-8) based on the meta-analysis of the 11 sources and via a candidate approach based on 13 suggestive early AMD variants from Holliday et al 2013 (P<0.05/13, additional 3,432 early AMD cases and 11,235 controls). For the novel AMD regions, we conducted in-silico follow-up analysis to prioritize causal genes and pathway analyses. ResultsWe identified 11 loci for early AMD, 9 novel and 2 known for early AMD. Most of these 11 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, APOE, C2, C3, CETP, PVRL2, TNFRSF10A, VEGFA), except two that were completely novel to any AMD. Among the 17 genes within the two novel loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. We found the presence or absence of an early AMD effect to distinguish known pathways of advanced AMD genetics (complement/lipid pathways or extracellular matrix metabolism, respectively). ConclusionsOur data on early AMD genetics provides a resource comparable to the existing data on advanced AMD genetics, which enables a joint view. Our large GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. The ability of early AMD effects to differentiate the major pathways for advanced AMD underscores the biological relevance of a joint view on early and advanced AMD genetics.

genetics↗

bioRxiv2018

Evaluation of the causal effect of fibrinogen on incident coronary heart disease via Mendelian randomization

BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.\n\nMethods and FindingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score incorporated data from 11 European-ancestry prospective cohorts to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI).\n\nIn single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.\n\nConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.\n\nAuthor SummaryInitial Mendelian Randomization (MR) analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches. This manuscript provides an important update to these initial analyses by incorporating larger sample sizes and employing multiple, modern multi-variant MR approaches to account for pleiotropy. We used incident cases to perform a MR study of the causal effect of fibrinogen on incident CHD and the nested outcome of myocardial infarction (MI) using an allele score approach. Then using data from a case-control genome-wide association study for CHD and MI we performed two sample MR analyses with multiple, pleiotropy robust approaches. Overall, the results indicated that associations between fibrinogen and CHD in observational studies are likely upwardly biased from any underlying causal effect. Single variant MR approaches show little evidence of a causal effect of fibrinogen on CHD or MI. Multi-variant MR analyses of fibrinogen on CHD indicate there may be a small positive effect, however this result needs to be interpreted carefully as the 95% confidence intervals were still consistent with a null effect. Multi-variant MR approaches did not suggest evidence of even a small causal effect of fibrinogen on MI.

genetics↗