FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.

BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer. OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach. METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing. RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10-8 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10-4 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels. CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.

Discovering genetic interactions bridging pathways in genome-wide association studies.

Genetic interactions have been reported to underlie phenotypes in a variety of systems, but the extent to which they contribute to complex disease in humans remains unclear. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions, but existing methods for identifying them from GWAS data tend to focus on testing individual locus pairs, which undermines statistical power. Importantly, a global genetic network mapped for a model eukaryotic organism revealed that genetic interactions often connect genes between compensatory functional modules in a highly coherent manner. Taking advantage of this expected structure, we developed a computational approach called BridGE that identifies pathways connected by genetic interactions from GWAS data. Applying BridGE broadly, we discover significant interactions in Parkinson's disease, schizophrenia, hypertension, prostate cancer, breast cancer, and type 2 diabetes. Our novel approach provides a general framework for mapping complex genetic networks underlying human disease from genome-wide genotype data.

Heritability of Vascular Structure and Function: A Parent-Child Study.

BACKGROUND: Understanding the heritable contribution of vascular measures, from parent to offspring, may aid in risk stratification and atherosclerosis prevention efforts. We hypothesized that measures of vascular structure and function would be heritable in this cohort of parents and their adolescent offspring. METHODS AND RESULTS: High-resolution ultrasound scans of the brachial and carotid arteries were obtained in parents (n=558) and their offspring (n=369). Lumen diameter and flow-mediated dilation were measured in the brachial artery. Intima-media thickness, lumen diameter, incremental elastic modulus, diameter distensibility, and cross-sectional distensibility were measured, and carotid cross-sectional compliance was measured in the carotid artery. Carotid-radial pulse wave velocity was obtained using SphygmoCor®. Heritability analysis (h2, expressed as %) using Sequential Oligogenic Linkage Analysis Routines was performed on the entire cohort and adjusted for age, sex, race, body-mass index, smoking, and mean arterial pressure. Data are presented as mean±SE. Measures of brachial artery diameter (h2=25±9%, P=0.001), lumen diameter (h2=55±9%, P<0.001), intima-media thickness (h2=29±13%, P=0.014), diameter distensibility (h2=28±7%, P<0.001), cross-sectional distensibility (h2=27±7%, P<0.001), and pulse wave velocity (h2=26±9%, P<0.001) were significantly heritable. Flow-mediated dilation and incremental elastic modulus were not significantly heritable. Similar associations were observed in analysis restricted to siblings and complete Trios (mother, father, and child). CONCLUSIONS: These data show that the majority of noninvasive measures of vascular structure and function are heritable, suggesting that measurement of these subclinical risk factors in parents may be helpful in assessing childhood risk for future cardiovascular disease.

Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.

Non-redundant summary scores applied to the North American Rheumatoid Arthritis Consortium dataset.

After performing a genome-wide association study, it is often difficult to know which regions to follow up, especially when no one marker reaches genome-wide significance. Researchers frequently focus on their top N findings, knowing that true associations may be buried deeper in the list. Others focus on genes or regions that have multiple markers showing evidence of association. However, these markers are often in high linkage disequilibrium with one another (r2 > 0.80), which indicates that these additional markers are providing redundant information. I propose a novel method that identifies regions with multiple lines of evidence, by down-weighting the contribution of additional markers in proportion to pairwise linkage disequilibrium. I have used this non-redundant summary score in my analysis of the North American Rheumatoid Arthritis Consortium dataset released as part of Genetic Analysis Workshop 16. Three regions were identified that had a genome-wide empirical p-value less than 0.01, including one novel region on chromosome 20 near the KCNB1 and PTGIS genes.

Hearing impairment susceptibility in elderly men and the DFNA18 locus.

OBJECTIVE: To identify any chromosomal region that shows evidence for linkage to age-related hearing loss in humans. DESIGN: Evaluation of genetic linkage using sibling-pair methods for hearing loss collected via self-report questionnaire and markers from a genome screening collected from a population-based representative sample of male fraternal twins born from 1917 to 1927. SUBJECTS: Members of a group of 6108 World War II and Korean War veteran twins (2059 complete pairs) who completed a health history questionnaire at a mean age of 74.3 years (range, 69-82 years). A subset of 711 twins (343 complete pairs) later provided a blood sample for DNA extraction in a study of genetic factors in healthy aging. Among the complete pairs were approximately 160 fraternal twins; 50 of these pairs were concordant for age-related hearing loss with at least 1 co-twin reporting bilateral hearing loss and with marker data available for analysis. RESULTS: A region suggestive of linkage was found on chromosome 3q, with a logarithm of the odds score of 2.5 in the same region of this chromosome where the DFNA18 locus resides, which has been reported to cause a form of progressive hereditary hearing loss. CONCLUSIONS: To our knowledge, this is the first sample from the general population that has been used in a genome screening for qualitative hearing loss. The results, if confirmed, suggest that genetic variation in the region of DFNA18 may be responsible for hearing loss with age in the general population.