The genomics of transplant-related outcomes and familial renal disease

Chronic kidney disease (CKD) is a growing global health concern with an age-standardized global prevalence of approximately 10%. Of those with CKD, approximately 2% will go on to require renal replacement therapy within any given 5-year period. Renal transplantation is accepted as the most clinically- and cost-effective treatment for end-stage kidney failure. In this thesis, we set out to examine the impact of common genetic variation on renal transplant function as well as a common post-transplant complication: non-melanoma skin cancer. We also aimed to examine a common form of CKD, IgA nephropathy, in a familial context using next generation sequencing techniques. We demonstrated that polygenic (but not single variant) effects of common genetic variation found in both the kidney donor and recipient impacts the function of the renal allograft in the early stages post-transplant. We also illustrated how measures of post-transplant renal outcomes do not correlate with the level of shared genetic ancestry between unrelated kidney donors and recipients in a cohort of European, deceased-donor transplants. We also showed that polygenic (but not single variant) effects of common genetic variation impacts both whether or not an individual develops post-transplant non-melanoma skin cancer but also, the speed at which they develop non-melanoma skin cancer. Finally, in our exome sequencing analysis of familial IgAN, we found that a number of Irish families carried rare, damaging and potentially disease-causing mutations in type IV collagen-related genes, known to cause kidney disease. In summary, this thesis demonstrates the impact of genetic variation on both kidney disease and transplant outcomes

Polygenic risk score of non‐melanoma skin cancer predicts post‐transplant skin cancer across multiple organ types

Polygenic risk scores (PRS) calculated from genome‐wide association studies (GWAS) of non-melanoma skin cancer (NMSC) in a general, non-transplant setting, have recently been shown to predict risk of, and time to post-renal transplant skin cancer. In this study, we set out to test these findings in a cohort of heart, lung and liver transplant patients to see if these scores could be applied across different organ transplant types. Using the PRS from Stapleton et al. (2018), PRS were calculated for each sample across a European ancestry heart, lung and liver transplant cohorts (n = 523) and tested as predictors time to NMSC post-transplant. The top PRS, squamous cell carcinoma (SCC) pT1x10-5, (n SNPs= 1953), SCC pT1x10-6 and SCC pT1x10-6 (n SNPs = 1061) was significantly predictive in the time to NMSC, SCC and basal cell carcinoma (BCC) analysis across organ (p = 0.006, 0.02 and 0.02 respectively). We observed here a similar direction of effect and effect size [NMSC HR = 1.31(1.08-1.59)] to that in the original, discovery study, with increased polygenic burden leading to a faster time to developing NMSC. In summary, we found that PRS of NMSC calculated from GWAS of NMSC in non-transplant populations independently replicated in this cohort of heart, lung and liver transplant.</p

A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

Objective: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. Methods: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). Results: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. Significance: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.</p

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort

Renal transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of NMSC in a general, nontransplant setting, can predict risk of, and time to posttransplant skin cancer. Genetic variants, reaching predefined P-value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) nontransplant GWAS. Using these GWAS, BCC and SCC PRS were calculated for each sample across three European ancestry renal transplant cohorts (n = 889) and tested as predictors of case:control status and time to NMSC posttransplant. BCC PRS calculated at P-value threshold 1 × 10 −5 was the most significant predictor of case:control status of NMSC posttransplant (OR = 1.61; adjusted P =.0022; AUC [full model adjusted for clinical predictors and PRS] = 0.81). SCC PRS at P-value threshold 1 × 10 −5 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10 −7 ; HR = 1.41, concordance [full model] = 0.74). PRS of nontransplant NMSC is predictive of case:control status and time to NMSC posttransplant. These results are relevant to how genomics can risk stratify patients to help develop personalized treatment regimens

A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy.Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum.Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found.Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.</p