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PubMed | University of Minnesota, University of Newcastle, University of Sfax, Cardiovascular Genetics and Genomics Group and 67 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including 120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

PubMed | University of Nottingham, St George's, University of London, MRC Human Genetics Unit, Swiss Tropical and Public Health Institute and 34 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10s role in influencing lungs susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

Corley J.,University of Edinburgh | Jia X.,Health Services Research Unit | Kyle J.A.M.,University of Aberdeen | Gow A.J.,University of Edinburgh | And 7 more authors.
Psychosomatic Medicine | Year: 2010

Objective: To investigate the association between caffeine consumption and cognitive outcomes in later life. Methods: Participants were 923 healthy adults from the Lothian Birth Cohort 1936 Study, on whom there were intelligence quotient (IQ) data from age 11 years. Cognitive function at age 70 years was assessed, using tests measuring general cognitive ability, speed of information processing, and memory. Current caffeine consumption (using multiple measures of tea, coffee, and total dietary caffeine) was obtained by self-report questionnaire, and demographic and health information was collected in a standardized interview. Results: In age-and sex-adjusted models, there were significant positive associations between total caffeine intake and general cognitive ability and memory. After adjustment for age 11 IQ and social class, both individually and together, most of these associations became nonsignificant. A robust positive association, however, was found between drinking ground coffee (e.g., filter and espresso) and performance on the National Adult Reading Test (NART, p =.007), and the Wechsler Test of Adult Reading (WTAR, p =.02). No gender effects were observed, contrary to previous studies. Generally, higher cognitive scores were associated with coffee consumption, and lower cognitive scores with tea consumption, but these effects were not significant in the fully adjusted model. Conclusions: The present study is rare in having childhood IQ in a large sample of older people. The results suggest that the significant caffeine intake-cognitive ability associations are bidirectional-because childhood IQ and estimated prior IQ are associated with the type of caffeine intake in old age-and partly confounded by social class. Copyright © 2010 by the American Psychosomatic Society.

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