Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOA Show more
Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the "synaptic PRS" in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%-6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset. Show less
Fatty acids, in particular omega-3 fatty acids, have been found to affect behavior and cognition both directly and indirectly. Evidence to suggest a link with attention-deficit/hyperactivity disorder Show more
Fatty acids, in particular omega-3 fatty acids, have been found to affect behavior and cognition both directly and indirectly. Evidence to suggest a link with attention-deficit/hyperactivity disorder (ADHD) derives from three key areas: 1) animal dietary restriction studies observed increased locomotive hyperactivity and reduced cognitive ability in offspring; 2) animal dietary studies indicate alterations in the dopamine pathway; and 3) human studies report reduced plasma omega-3 fatty acids in ADHD subjects. We investigated three genes that encode essential enzymes (desaturases) for the metabolism of fatty acids by scanning for genetic association between 45 single nucleotide polymorphisms (SNPs) and ADHD. Our findings suggest a significant association of ADHD with SNP rs498793 (case-control p = .004, odds ratio [OR] 1.6, 95% confidence interval [CI] 1.15-2.23; transmission disequilibrium test [TDT] p = .014, OR 1.69) in the fatty acid desaturase 2 (FADS2) gene. As alcohol is known to decrease the activities of these desaturase enzymes, we also tested for interactions between ADHD subjects' genotypes and maternal use of alcohol during pregnancy. Two SNPs in the fatty acid desaturase 1 (FADS1) gene were nominally associated with ADHD only in the prenatal alcohol-exposed group of children; formal test for interaction was not significant. These preliminary findings are suggestive of an association between FADS2 and ADHD. Show less