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Venous thromboembolism (VTE) is the third most common life-threatening cardiovascular condition in the United States, with African Americans (AAs) having a 30% to 60% higher incidence compared with other ethnicities. The mechanisms underlying population differences in the risk of VTE are poorly understood. We conducted the first genome-wide association study in AAs, comprising 578 subjects, followed by replication of highly significant findings in an independent cohort of 159 AA subjects. Logistic regression was used to estimate the association between genetic variants and VTE risk. Through bioinformatics analysis of the top signals, we identified expression quantitative trait loci (eQTLs) in whole blood and investigated the messenger RNA expression differences in VTE cases and controls. We identified and replicated single-nucleotide polymorphisms on chromosome 20 (rs2144940, rs2567617, and rs1998081) that increased risk of VTE by 2.3-fold (P< 6 × 10(-7)). These risk variants were found in higher frequency among populations of African descent (>20%) compared with other ethnic groups (<10%). We demonstrate that SNPs on chromosome 20 are cis-eQTLs for thrombomodulin (THBD), and the expression of THBD is lower among VTE cases compared with controls (P= 9.87 × 10(-6)). We have identified novel polymorphisms associated with increased risk of VTE in AAs. These polymorphisms are predominantly found among populations of African descent and are associated with THBD gene expression. Our findings provide new molecular insight into a mechanism regulating VTE susceptibility and identify common genetic variants that increase the risk of VTE in AAs, a population disproportionately affected by this disease.
Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3 to 20 years later. Although anti-thyroperoxidase (anti-TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications.
© 2014 American Society for Bone and Mineral Research.
Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.
To identify new genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in east Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples, including up to 5,358 cases and 5,922 controls. We identified four SNPs with association P values of 8.58 × 10(-7) to 3.77 × 10(-10) in the combined analysis of all east Asian samples. Three of the four were replicated in a study conducted in 26,060 individuals of European descent, with combined P values of 1.22 × 10(-10) for rs647161 (5q31.1), 6.64 × 10(-9) for rs2423279 (20p12.3) and 3.06 × 10(-8) for rs10774214 (12p13.32 near the CCND2 gene), derived from meta-analysis of data from both east Asian and European-ancestry populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC.
BACKGROUND - Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants.
METHODS - We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold-truncated product of P-values for each locus.
RESULTS - While no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (P(emp)<2×10⁻⁵) based on the minimum P-value and truncated-product methods, respectively.
CONCLUSIONS - Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci.
Mutations in SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of SHANK3 to the pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.
UNLABELLED - A genome-wide linkage scan was performed in a sample of 79 multiplex pedigrees to identify genomic regions linked to femoral neck cross-sectional geometry. Potential quantitative trait loci were detected at several genomic regions, such as 10q26, 20p12-q12, and chromosome X.
INTRODUCTION - Bone geometry is an important determinant of bone strength and osteoporotic fractures. Previous studies have shown that femoral neck cross-sectional geometric variables are under genetic controls. To identify genetic loci underlying variation in femoral neck cross-sectional geometry, we conducted a whole genome linkage scan for four femoral neck cross-sectional geometric variables in 79 multiplex white pedigrees.
MATERIALS AND METHODS - A total of 1816 subjects from 79 pedigrees were genotyped with 451 microsatellite markers across the human genome. We performed linkage analyses on the entire data, as well as on men and women separately.
RESULTS - Significant linkage evidence was identified at 10q26 for buckling ratio (LOD = 3.27) and Xp11 (LOD = 3.45) for cortical thickness. Chromosome region 20p12-q12 showed suggestive linkage with cross-sectional area (LOD = 2.33), cortical thickness (LOD = 2.09), and buckling ratio (LOD = 1.94). Sex-specific linkage analyses further supported the importance of 20p12-q12 for cortical thickness (LOD = 2.74 in females and LOD = 1.88 in males) and buckling ratio (LOD = 5.00 in females and LOD = 3.18 in males).
CONCLUSIONS - This study is the first genome-wide linkage scan searching for quantitative trait loci underlying femoral neck cross-sectional geometry in humans. The identification of the genes responsible for bone geometric variation will improve our knowledge of bone strength and aid in development of diagnostic approaches and interventions for osteoporotic fractures.
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, accounting for 5%-8% of all pediatric malignancies. RMS can be categorized into several subtypes, including embryonal RMS (ERMS), the botryoid and spindle cell variants of ERMS, and alveolar RMS (ARMS). The t(2;13)(q35;q14) and the variant t(1;13)(p36;q14) are seen in a majority of ARMS cases. In contrast, the embryonal subtype of rhabdomyosarcoma has not been associated with a recurring chromosomal translocation. We describe here a novel chromosomal t(2;20)(q35;p12) occurring in a case of childhood RMS with embryonal histology. It is notable that this translocation harbors breakpoints at or near the locus of the PAX3 gene, which is involved in the most common recurring translocation associated with ARMS.
Mite sensitivity has been reported to be a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome scan using mite reactivity (Dermatophagoides Pteronyssinus (Der p) and Dermatophagoides farinae (Der f)) as the phenotype was conducted. In 287 CSGA families, 122 were informative for linkage. Evidence supporting linkage was observed for regions on chromosome 19 (D19S591, lod=2.43, P=0.0008; D19S1037, lod=1.57, P=0.007) and chromosome 20 (D20S473/D20S604, lod=1.41, P=0.01). All three ethnic groups appeared to contribute to the evidence for linkage on chromosome 20. African-American families gave strongest support for linkage on chromosomes 3 (D3S2409, lod=1.33, P=0.01), 12 (D12S373, lod=1.51, P=0.008) and 18 (ATA82B02, lod=1.32, P=0.01). Caucasian families showed strong evidence for linkage on chromosome 19 (D19S591, lod=3.51, P=0.00006). Hispanic families supported linkage on chromosomes 11 (D11S1984, lod=1.56, P=0.007), 13 (D13S787, lod=1.30, P=0.01) and 20 (D20S470, lod=1.71, P=0.005). These results suggest that multiple genes may be involved in controlling skin reactivity to Dermatophoigoies.