A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

OBJECTIVE: Levetiracetam (LEV) is an effective anti-seizure 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 behavioural ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioural 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 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-ADR. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to controls (p = 0.0097, estimate = 0.4886). 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

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

Genetic variation across the HLA is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the HLA is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with post‐transplant eGFR at different time‐points, out to 5‐years post‐transplantation. We conducted GWAS meta‐analyses across 10,844 donors and recipients from five European ancestry cohorts. We also analysed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with non‐transplant eGFR, on post‐transplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year post‐transplant. 32% of the variability in eGFR at 1‐year post‐transplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR post‐transplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a post‐transplant context. Despite PRS being a significant predictor of eGFR post‐transplant, the effect size of common genetic factors is limited compared to clinical variables

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application

Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale

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

The relationship between donor-recipient genetic distance and long-term kidney transplant outcome [version 1; peer review: 3 approved]

Background: We set out to quantify shared genetic ancestry between unrelated kidney donor-recipient pairs and test it as a predictor of time to graft failure. Methods: In a homogenous, unrelated, European cohort of deceased-donor kidney transplant pairs (n pairs = 1,808), we calculated, using common genetic variation, shared ancestry at the genic (n loci=40,053) and genomic level. We conducted a sub-analysis focused on transmembrane protein coding genes (n transcripts=8,637) and attempted replication of a previously published nonsynonymous transmembrane mismatch score. Measures of shared genetic ancestry were tested in a survival model against time to death-censored graft failure Results: Shared ancestry calculated across the human leukocyte antigen (HLA) significantly associated with graft survival in individuals who had a high serological mismatch (n pairs = 186) with those who did not have any HLA mismatches indicating that shared ancestry calculated specific loci can capture known associations with genes impacting graft outcome. None of the other measures of shared ancestry at a genic level, genome-wide scale, transmembrane subset or nonsynonymous transmembrane mismatch score analysis were significant predictors of time to graft failure. Conclusions: In a large unrelated, deceased-donor European ancestry renal transplant cohort, shared donor-recipient genetic ancestry, calculated using common genetic variation, has limited value in predicting transplant outcome both on a genomic scale and at a genic level (other than at the HLA loci). </p