Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

in Nature Genetics (2019), 51(3), 414

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of ... [more ▼]

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A$\beta$ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education. [less ▲]

The miRNome of Alzheimer's disease: consistent downregulation of the miR-132/212 cluster

in Neurobiology of Aging (2016), 50

MicroRNAs (miRNAs) are small noncoding RNA molecules, with essential functions in RNA silencing and post-transcriptional regulation of gene expression. miRNAs appear to regulate the development and ... [more ▼]

MicroRNAs (miRNAs) are small noncoding RNA molecules, with essential functions in RNA silencing and post-transcriptional regulation of gene expression. miRNAs appear to regulate the development and function of the nervous system. Alterations of miRNA expression have been associated with Alzheimer's disease (AD). To characterize the AD miRNA signature, we examined genome-wide miRNA and mRNA expression patterns in the temporal cortex of AD and control samples. We validated our miRNA results by semiquantitative real-time polymerase chain reaction (PCR) in independent prefrontal cortex. Furthermore, we separated gray and white matter brain sections to identify the cellular origin of the altered miRNA expression. We observed genome-wide downregulation of hsa-miR-132-3p and hsa-miR-212-3p in AD with a stronger decrease in gray matter AD samples. We further identified 10 differently expressed transcripts achieving genome-wide levels of significance. Significantly deregulated miRNAs and mRNAs were correlated and examined for potential binding sites (in silico). This miRNome-wide study in AD provides supportive evidence and corroborates an important contribution of miR-132/212 and corresponding target mRNAs to the pathogenesis of AD. [less ▲]

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

in Nature Genetics (2013), 45