Researchers Use GWAS to Identify Novel Loci Associated with Kidney Function

After conducting further genome-wide association studies (GWAS), we will be able to inform communities about the potential implications of gene expression in their kidneys, said Adriana Hung, MD, MPH, associate professor of medicine at Vanderbilt University in an interview with Bryce Rowan, a statistical genetic analyst.

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How did you carry out the genome-wide analyses for this study and what were the main findings?

Dr. Hung:We're trying to learn about genetic determinants of kidney function in minority groups. As we are all aware, the progression of kidney disease to end stage renal disease (ESRD) is 4-fold higher in the African American population and it also affects the Latino population at a higher rate. We wanted to learn genetic variants in addition to APOL 1 that played a role in faster progression to end stage renal disease so that we could complement the information that we get from using just APOL 1 and actually the sickle cell trait. We took advantage of the Million Veteran Program which is the largest biobank in the world currently. We used a sample size of about 82,000 African Americans. The genetic analysis, per se, is a standard approach. We just used the linear additive model to a cross-sectional approach of kidney function, or eGFR that was measured at enrollment. We were able to adjust for BMI, age, gender, and sex and then principal components of ancestry. What really is great about these analyses is the sample size. We're hoping that in the future, we can have even further participants in the minorities analysis. Also, because this is linked to the electronic health record, we have the opportunity which we're not presenting in this current presentation, of doing many post-GWAS analyses such as phenome-WAS and genetically predicted gene expression, which helps us to bring all those associations that we see in the GWAS to a more translational context, and be able to inform a little more of the implication of the different variants that we are getting from the genome wide association analysis. In addition to the African American genome wide association studies, you will learn that in this particular study, or at this particular meeting, we are presenting complimentary analysis, which include APOL 1 interaction by Cassianne Robinson-Cohen, and we're also doing an analysis and a GWAS for Hispanics. All of these different genome wide association studies do complement each other and help to bring further that very particular interest of ours, which is just learning what other genetic variants are unique to minority groups, and have impact in the higher risk of progressing to end stage renal disease.

Rowan:We also had, during the GWAS we used different methods. Our statistician brought up something called effective sample size, which was just a nice way to have nicer Q-Q plot results, but also to generate more results. We were able to capture the sickle cell trait, we were able to actually get some of these rarer variants in there via that method as well. Then we also were able to use genome-wide complex trait analysis, conditional and joint analysis (GCTA cojo) to actually do independent hits from our analyses. And that's what will be presented are the independent hits.

In your study, you replicated over 19 previously identified loci and 3 novel loci associated with kidney function. Can you elaborate on the clinical relevance of these findings?

Rowan: Well, for the ones that were already identified, replication is a huge deal. Of course, seeing APOL 1 pop up again, and GATM and some of these others, sickle cell trait, that's always a positive sign too, because that means that we know these aren't spurious associations. These are things that are already identified in the literature. The novel loci, a lot of them have different cellular level effects...They give new breadth and expand the study out more. Some of them aren't seen in kidney disease as much, some of them are seen more in cardiovascular issues. So it's an interesting, it's just an interesting way to explore the field more and kind of see how things link up.

Dr. Hung: Regarding the 3 novel loci, one of them, is known for being associated with accelerated atherosclerosis, and that is the ABCA1. That's an important link, as we know that patients with chronic kidney disease have an accelerated atherosclerosis process that we're still trying to figure out the mechanisms and pathways to see if we can change that. For the other 2 loci, we're not sure right now of the mechanisms that link them to chronic kidney disease. However, as I mentioned before, we're doing many post translational analyses, including the genetically predicted gene expression in kidney tissue. We also are linking them to phenome-wide association analyses. We're using them against other drug relationship databases. These types of approaches are going to help us to figure out these other 2 loci, how are they related to gene expression in the entire body, in the kidney, so that we can understand their mechanisms. I guess that in the near future, after all these post-GWAS analyses, we will be able to inform the community about the potential implications that they have in the gene expression of other kidneys, or if they have functional implications on their own.