A program of research in respiratory and cardiovascular genetic epidemiology
Lead Research Organisation:
University of Leicester
Department Name: Health Sciences
Abstract
Chronic obstructive pulmonary disease and high blood pressure affect a high proportion of adults in the UK. This program, involving collaborators from several UK and international centres, aims to identify the genetic causes of these disorders. By comparing measures of lung function in tens of thousands of individual study participants for variants at each of millions of different sites across the human genome, we can identify variants associated with lung disease. We will study the impact of these variants in more detail, examining their effect on lung growth, on decline in lung function with age or with disease, on effects of smoking and on response to treatment. Similar discovery and follow-up studies will be undertaken for blood pressure. We can also use the identified genetic variants to tell us more about modifiable non-genetic influences on disease, such as whether dietary deficiency in folate causes high blood pressure. In most cases, we do not expect these variants to accurately predict an individual‘s risk of developing disease, but we do expect the genes identified to give important clues about how the diseases are caused and advance our understanding of how they might be more effectively prevented and treated.
Technical Summary
Aims
(1) To identify sequence and structural variants in the human genome associated with respiratory function and chronic obstructive pulmonary disease
(2) To identify human genomic variants associated with blood pressure and related cardiovascular traits.
Main objectives
1.1. To discover common single nucleotide polymorphisms (SNPs) associated with pulmonary function
1.2. To identify rare SNPs associated with COPD and pulmonary function in existing data and from resequencing novel loci.
1.3. To study common and rare copy number variants (CNVs) associated with pulmonary function.
1.4. To assess the role of genomic variants from 1.1 to 1.3 in: development in pulmonary function, decline in pulmonary function; pulmonary function in diseased individuals; airway response to beta-2 agonists, effect modification of tobacco smoking; Mendelian randomization studies aimed at understanding potentially modifiable intermediate pathways underlying lung function.
2.1. To discover common single nucleotide polymorphisms (SNPs) associated with blood pressure.
2.2. To study common and rare copy number variants (CNVs) associated with blood pressure.
2.3. To assess the role of blood pressure associated variants from 2.1 and 2.2 in: longitudinal change in blood pressure; circadian variation in ambulatory BP; Mendelian randomization studies to assess causal pathways influencing blood pressure. Mendelian randomization studies will utilise variants from 1.1 to 1.3 to investigate the causal mechanisms for the reported association between lung function and cardiovascular disease.
Design and methodology
The research will utilise existing genome-wide association study (GWAS) data in very large sample sizes and will utilise new publicly available data to impute untyped variants (1.1, 2.1). I will employ novel statistical approaches for the detection of rare variant associations (1.2) and deep resequencing (1.2) for regions identified from GWAS. I will further develop methods to study CNVs genome-wide and apply these to large study populations to test CNV associations in 1.3 and 2.2. Causal pathways underlying these traits will be investigated (1.4, 2.3) using carefully phenotyped populations, longitudinal analyses employing generalised linear mixed models we have previously developed, and Mendelian randomization analyses in very large populations using methods we have developed in the group.
Scientific and medical opportunities
Well-designed, adequately powered and carefully analysed genetic association studies can inform understanding of the aetiological pathways underlying disease causation and progression, and may highlight potential targets for prevention and treatment. Disease-associated genetic variants can also be used in traditional epidemiological studies (Mendelian randomization) to inform understanding of intermediate pathways that may be amenable to public health intervention.
(1) To identify sequence and structural variants in the human genome associated with respiratory function and chronic obstructive pulmonary disease
(2) To identify human genomic variants associated with blood pressure and related cardiovascular traits.
Main objectives
1.1. To discover common single nucleotide polymorphisms (SNPs) associated with pulmonary function
1.2. To identify rare SNPs associated with COPD and pulmonary function in existing data and from resequencing novel loci.
1.3. To study common and rare copy number variants (CNVs) associated with pulmonary function.
1.4. To assess the role of genomic variants from 1.1 to 1.3 in: development in pulmonary function, decline in pulmonary function; pulmonary function in diseased individuals; airway response to beta-2 agonists, effect modification of tobacco smoking; Mendelian randomization studies aimed at understanding potentially modifiable intermediate pathways underlying lung function.
2.1. To discover common single nucleotide polymorphisms (SNPs) associated with blood pressure.
2.2. To study common and rare copy number variants (CNVs) associated with blood pressure.
2.3. To assess the role of blood pressure associated variants from 2.1 and 2.2 in: longitudinal change in blood pressure; circadian variation in ambulatory BP; Mendelian randomization studies to assess causal pathways influencing blood pressure. Mendelian randomization studies will utilise variants from 1.1 to 1.3 to investigate the causal mechanisms for the reported association between lung function and cardiovascular disease.
Design and methodology
The research will utilise existing genome-wide association study (GWAS) data in very large sample sizes and will utilise new publicly available data to impute untyped variants (1.1, 2.1). I will employ novel statistical approaches for the detection of rare variant associations (1.2) and deep resequencing (1.2) for regions identified from GWAS. I will further develop methods to study CNVs genome-wide and apply these to large study populations to test CNV associations in 1.3 and 2.2. Causal pathways underlying these traits will be investigated (1.4, 2.3) using carefully phenotyped populations, longitudinal analyses employing generalised linear mixed models we have previously developed, and Mendelian randomization analyses in very large populations using methods we have developed in the group.
Scientific and medical opportunities
Well-designed, adequately powered and carefully analysed genetic association studies can inform understanding of the aetiological pathways underlying disease causation and progression, and may highlight potential targets for prevention and treatment. Disease-associated genetic variants can also be used in traditional epidemiological studies (Mendelian randomization) to inform understanding of intermediate pathways that may be amenable to public health intervention.