rs4420638

Case-control study of 673 preterm birth (PTB) cases vs 1,119 controls across four maternal cohorts testing 35 SNPs in cardiovascular, inflammatory, and metabolic disease genes. Found 13 statistically significant associations with PTB (P<0.05), more than expected by chance (binomial P=0.02). Most significant was HLA-DQA1 rs9272346 G allele protective effect in US White mothers (P=0.02, OR=0.65, 95% CI 0.46-0.94), which nominally replicated in Danish cohort (P=0.02, OR=0.85, 95% CI 0.75-0.97) but lost significance after correction for multiple testing.

A genome-wide association study of 725 deceased subjects identified genetic susceptibility loci for Alzheimer's disease neuritic plaque pathology. Beyond APOE and CR1, the study found ABCA7 (rs3764650, p=0.03) and CD2AP (rs9349407, p=0.03) associated with increased neuritic plaque burden. Notably, a novel APP locus variant (rs2829887, p=3.3×10⁻⁶) was associated with neuritic plaques and β-amyloid load in postmortem samples and independently replicated in cognitively normal PET imaging cohorts, implicating common genetic variation in amyloid pathology at pre-symptomatic AD stages.

This association study of 732 chronic hepatitis C patients examined polymorphisms in the TOMM40-APOE genomic region. rs7412 was significantly associated with serum apolipoprotein E levels (p=2.3×10⁻¹¹), explaining 7% of variance. Among IL28B-CC patients (n=196), rs429358 and TOMM40 '523' polymorphisms together explained 12% of variance in apolipoprotein B levels. Patients homozygous for APOE e3 isoform showed >2-fold increased odds of F2-F4 hepatic fibrosis (p=1.8×10⁻⁵), independent of lipid levels.

This comprehensive genome-wide association study examined genetic variants contributing to late-onset Alzheimer's disease (AD) in 513 African American cases and 496 controls, plus replication in 5 white cohorts. The APOE ε4 allele showed strong association (P=9.69×10⁻²³), and after adjusting for APOE, rs6859 in PVRL2 remained significantly associated (P=0.0087). The study found associations with variants in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, though effect directions sometimes differed from white populations. Novel associations with suggestive evidence were identified in PROX1, CNTNAP2, STK24, and other genes, though not replicated in whites.

This case-control study attempted to replicate the association of TOMM40 polyT polymorphism (rs10524523) with Alzheimer's disease risk and age at onset. In a large series of 1594 LOAD cases and 1190 controls, the study failed to replicate the previously reported association with age at onset but found a significant association between rs10524523 and risk for LOAD among APOE 33 homozygotes in the opposite direction (OR=0.78, 95% CI=0.65-0.95; p=0.004, allele frequencies 0.41 vs 0.48 in cases vs controls). No association was found between rs10524523 and CSF biomarker levels (tau, phosphorylated tau, Aβ42) or TOMM40/APOE gene expression.

This 3-stage genome-wide association meta-analysis study identified 5 novel and confirmed loci associated with late-onset Alzheimer's disease across over 35,000 individuals. The study discovered two new genome-wide significant loci: rs744373 in BIN1 (OR 1.13, p=1.59×10⁻¹¹) and rs597668 near EXOC3L2 (OR 1.18, p=6.45×10⁻⁹), and confirmed three previously reported loci in APOE (OR 2.53, p=1.04×10⁻²⁹⁵), CLU (OR 0.85, p=1.62×10⁻¹⁶), and PICALM (OR 0.89, p=3.16×10⁻¹²). These findings were validated in an independent Spanish replication sample of 2,349 individuals.

This follow-up study of genomewide association findings tested 4 putative Alzheimer's disease susceptibility loci from prior GWA studies in 4,007 DNA samples from 1,299 families with AD. Only rs7101429 in GAB2 showed significant evidence of association (P = .002), with a protective effect (OR = 0.76, 95% CI 0.62-0.94). The other 3 loci (GOLM1, chromosome 15q, and chromosome 9p) did not show consistent evidence of association across the datasets.

This review examines genome-wide association studies (GWAS) methodology and challenges in genetic dissection of complex traits. The authors review study design, genotyping platforms, quality control, and statistical analysis approaches for GWAS, citing key examples including associations of rs1051730 (CHRNA3) with lung cancer and nicotine dependence, rs10484554 (HLA-C) with AIDS nonprogression and psoriasis, rs2476601 (PTPN22) with Crohn's disease and type 1 diabetes, and BCL11A variants with fetal hemoglobin levels.

Genome-wide association study identified five genetic loci influencing C-reactive protein (CRP) levels: rs6700896 in LEPR (-14.7% per allele, OR 1.06 for CHD), rs4537545 in IL6R (-10.8%, OR 0.94 for CHD), rs7553007 in CRP locus (-20.7%, OR 0.98 for CHD), rs1183910 in HNF1A (-13.6%), and rs4420638 in APOE-CI-CII (-21.8%, OR 1.16 for CHD). Mendelian randomization analysis of 28,112 CHD cases and 100,823 controls found no causal association between CRP genetic variants and coronary heart disease (OR 1.00, 95% CI 0.97-1.02), arguing against CRP having a causal role in atherosclerosis.

This linkage study of 417 affected sibling pairs with Alzheimer's disease from Sweden/Norway, UK, and USA examined chromosome 19q13. The strongest linkage peak (Zlr=3.28, P=0.036) was located 1 Mb from APOE. APOE ε4 alleles explained the linkage in the whole sample and UK/USA subsamples, though the Swedish sample showed marginal evidence of additional linkage. Age at onset had a significant effect on the linkage peak (lod increase=3.31, P=0.002), partially explained by APOE genotypes.