ABSTRACT
In the majority of patients, epilepsy is a complex disorder with multiple susceptibility genes interacting with environmental factors. However, we understand little about its genetic risks. Here, we report the first genome-wide association study (GWAS) to identify common susceptibility variants of epilepsy in Chinese. This two-stage GWAS included a total of 1087 patients and 3444 matched controls. In the combined analysis of the two stages, the strongest signals were observed with two highly correlated variants, rs2292096 [G] [P= 1.0 × 10(-8), odds ratio (OR) = 0.63] and rs6660197 [T] (P= 9.9 × 10(-7), OR = 0.69), with the former reaching genome-wide significance, on 1q32.1 in the CAMSAP1L1 gene, which encodes a cytoskeletal protein. We also refined a previously reported association with rs9390754 (P= 1.7 × 10(-5)) on 6q21 in the GRIK2 gene, which encodes a glutamate receptor, and identified several other loci in genes involved in neurotransmission or neuronal networking that warrant further investigation. Our results suggest that common genetic variants may increase the susceptibility to epilepsy in Chinese.
Subject(s)
Asian People/genetics , Cytoskeletal Proteins/genetics , Epilepsy/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Genome-Wide Association Study , Humans , Male , Microtubule-Associated Proteins , Middle Aged , Odds Ratio , Young AdultABSTRACT
More women than men have Alzheimer's disease (AD). Retrospective studies suggested that hormone replacement therapy (HRT) might counteract this disparity by reducing the risk of developing dementia. However, a recent, large, prospective study revealed the puzzling result that HRT increased dementia risk. A review of the literature was conducted to generate hypotheses that might explain why more women than men have AD, and how HRT may increase dementia risk. Longer life span of women than men may be the largest factor in the preponderance of women with AD. Longer duration of disease, less vascular dementia, and less testosterone in women than men may also contribute somewhat. HRT might increase dementia risk by several mechanisms: greater risk of strokes, leading to dementia; use of medroxyprogesterone acetate and estrone, which might have somewhat different possible effects on neuronal and cerebrovascular function than may progesterone and estradiol; decrease of free testosterone which might protect against AD; a dose or delivery method perhaps producing drug levels that might lie outside a hypothetical beneficial range; and down-regulation of estrogen receptors on cholinergic neurons, possibly reducing cholinergic activity. Further study is required to discern by which of several possible mechanisms HRT increases dementia risk.
