Distinct genetic basis of common epilepsies and structural magnetic resonance imaging measures

Focal and generalized epilepsies are associated with robust differences in MRI measures of subcortical structures, grey matter and white matter. However, it is unknown whether such structural brain differences reflect the cause or consequence of epilepsy or its treatment. Analyses of common genetic variants underlying both common epilepsy and variability in structural brain measures can give further insights, since such inherited variants are not influenced by disease or treatment. Here, we performed genetic correlation analyses using data from the largest genome-wide association study (GWAS) on common epilepsy (n=27,559 cases and 42,436 controls) and GWAS on MRI measures of white (n=33,292) or grey matter (n=51,665). We did not detect any significant genetic correlation between any type of common epilepsy and any of 280 measures of grey matter, white matter or subcortical structures. These results suggest that there are distinct genetic bases underlying risk of common epilepsy and for structural brain measures. This would imply that the genetic basis of normal structural brain variation is unrelated to that of common epilepsy. Structural changes in epilepsy could rather be the consequence of epilepsy, its comorbidities or its treatment, offering a cumulative record of disease

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients