New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Recommendations for Publication of Genetic Association Studies in Arthritis & Rheumatism

Pathophysiology and treatment of rheumatic disease

Fine mapping the TAGAP risk locus in rheumatoid arthritis

A common allele at the TAGAP gene locus demonstrates a suggestive, but not conclusive association with risk of rheumatoid arthritis (RA). To fine map the locus, we conducted comprehensive imputation of CEU HapMap single-nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) of 5500 RA cases and 22 621 controls (all of European ancestry). After controlling for population stratification with principal components analysis, the strongest signal of association was to an imputed SNP, rs212389 (P 3.9 x 10(-8), odds ratio 0.87). This SNP remained highly significant upon conditioning on the previous RA risk variant (rs394581, P = 2.2 x 10(-5)) or on a SNP previously associated with celiac disease and type I diabetes (rs1738074, P = 1.7 x 10(-4)). Our study has refined the TAGAP signal of association to a single haplotype in RA, and in doing so provides conclusive statistical evidence that the TAGAP locus is associated with RA risk. Our study also underscores the utility of comprehensive imputation in large GWAS data sets to fine map disease risk alleles. Genes and Immunity (2011) 12, 314-318; doi:10.1038/gene.2011.8; published online 10 March 2011Pathophysiology and treatment of rheumatic disease

Genome-Wide Association Study and Comparison of Risk Alleles for Rheumatoid Arthritis in An Isolated Dutch Population

Pathophysiology and treatment of rheumatic disease

Associations of autoantibodies, autoimmune risk alleles, and clinical diagnoses from the electronic medical records in rheumatoid arthritis cases and nonrheumatoid arthritis controls

Pathophysiology and treatment of rheumatic disease

Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis.

The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases

Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway

Pathophysiology and treatment of rheumatic disease

Potential Of Integrating Human Genetics and Electronic Medical Records For Drug Discovery: The Example Of TYK2 and Rheumatoid Arthritis

Pathophysiology and treatment of rheumatic disease

META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IN CELIAC DISEASE AND RHEUMATOID ARTHRITIS IDENTIFIES FOURTEEN NON-HLA SHARED LOCI

Pathophysiology and treatment of rheumatic disease