Multilocus Heterozygosity and Coronary Heart Disease: Nested Case-Control Studies in Men and Women

Generalized allelic heterozygosity has been proposed to improve reproductive fitness and has been associated with higher blood pressure, but its association with chronic disease is not well characterized.Using the Affymetrix Genome-Wide Human 6.0 array, we performed whole genome scans in parallel case-control studies of coronary heart disease (CHD) nested in the Health Professionals Follow-up Study and Nurses' Health Study. We examined ~700,000 single nucleotide polymorphisms (SNPs) in 435 men with incident CHD and 878 matched controls and 435 women with incident CHD with 931 matched controls. We examined the relationship of genome-wide heterozygosity with risk of incident of CHD and with baseline levels of cardiovascular risk factors.In both cohorts, approximately 227650 (SD 2000) SNPs were heterozygous. The number of heterozygous SNPs was not related to risk of CHD in either men or women (adjusted odds ratios per 2000 heterozygous SNPs 1.01 [95% confidence interval, 0.91-1.13] in women and 0.94 [0.84-1.06] in men). We also found no consistent associations of genome-wide heterozygosity with levels of lipids, inflammatory markers, adhesion molecules, homocysteine, adiponectin, or body-mass index.In these parallel nested case-control studies, we found no relationship of multilocus heterozygosity with risk of CHD or its major risk factors. Studies in other populations are needed to rule out associations with lower levels of heterozygosity

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH

SNPsnap: a Web-based tool for identification and annotation of matched SNPs

Summary: An important computational step following genome-wide association studies (GWAS) is to assess whether disease or trait-associated single-nucleotide polymorphisms (SNPs) enrich for particular biological annotations. SNP-based enrichment analysis needs to account for biases such as co-localization of GWAS signals to gene-dense and high linkage disequilibrium (LD) regions, and correlations of gene size, location and function. The SNPsnap Web server enables SNP-based enrichment analysis by providing matched sets of SNPs that can be used to calibrate background expectations. Specifically, SNPsnap efficiently identifies sets of randomly drawn SNPs that are matched to a set of query SNPs based on allele frequency, number of SNPs in LD, distance to nearest gene and gene density. Availability and implementation: SNPsnap server is available at http://www.broadinstitute.org/mpg/snpsnap/. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Protein Interaction-Based Genome-Wide Analysis of Incident Coronary Heart Disease

BACKGROUND: Network-based approaches may leverage genome-wide association (GWA) analysis by testing for the aggregate association across several pathway members. We aimed to examine if networks of genes that represent experimentally determined protein-protein interactions are enriched in genes associated with risk of coronary heart disease (CHD). METHODS AND RESULTS: GWA analyses of ~700,000 SNPs in 899 incident CHD cases and 1,823 age- and sex-matched controls within the Nurses’ Health and the Health Professionals Follow-Up Studies were used to assign gene-wise p-values. A large database of protein-protein interactions (PPI) was used to assemble 8,300 unbiased protein complexes and corresponding gene-sets. Superimposed gene-wise p-values were used to rank gene-sets based on their enrichment in genes associated with CHD. After correcting for the number of complexes tested, one gene-set was overrepresented in CHD-associated genes (p-value=0.002). Centered on the beta-1-adrenergic receptor gene (ADRB1), this complex included 18 protein interaction partners that, so far, have not been identified as candidate loci for CHD. Five of the 19 genes in the top-complex are reported to be involved in abnormal cardiovascular system physiology based on knock-out mice (4-fold enrichment; p-value, Fisher’s exact test= 0.006). Ingenuity pathway analysis revealed that especially canonical pathways related to blood pressure regulation were significantly enriched in the genes from the top complex. CONCLUSIONS: The integration of a GWA study with PPI data successfully identifies a set of candidate susceptibility genes for incident CHD that would have been missed in single-marker GWA analysis

Novel Microcephalic Primordial Dwarfism Disorder Associated with Variants in the Centrosomal Protein Ninein

Microcephalic primordial dwarfism (MPD) is a rare, severe form of human growth failure in which growth restriction is evident in utero and continues into postnatal life. Single causative gene defects have been identified in a number of patients with MPD, and all involve genes fundamental to cellular processes including centrosome functions