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An analysis of 16 health-related quantitative traits in approximately 350,000 individuals reveals statistically significant associations between genome-wide homozygosity and four complex traits (height, lung function, cognitive ability and educational attainment); in each case increased homozygosity associates with a decreased trait value, but no evidence was seen of an influence on blood pressure, cholesterol, or ten other cardio-metabolic traits. Parental relatedness link to height and intelligence This consortium meta-analysis of 102 cohorts and more than 350,000 individuals investigates the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Focusing on 16 health-related quantitative traits, the authors find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in a second, general cognitive ability and educational attainment. In each case increased homozygosity associates with decreased trait value. No evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Homozygosity has long been associated with rare, often devastating, Mendelian disorders 1 , and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness 2 . However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power 3 , 4 . Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment ( P < 1 × 10 −300 , 2.1 × 10 −6 , 2.5 × 10 −10 and 1.8 × 10 −10 , respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples 5 , 6 , no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection 7 , this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and likely includes a subgroup that is biologically comparable to asthma. Studying asthma-associated gene expression changes in COPD could add insight into COPD pathogenesis and reveal biomarkers that predict a favorable response to corticosteroids. Objectives To determine whether asthma-associated gene signatures are increased in COPD and associated with asthma-related features. Methods We compared disease-associated airway epithelial gene expression alterations in an asthma cohort (n = 105) and two COPD cohorts (n = 237, 171). The T helper type 2 (Th2) signature (T2S) score, a gene expression metric induced in Th2-high asthma, was evaluated in these COPD cohorts. The T2S score was correlated with asthma-related features and response to corticosteroids in COPD in a randomized, placebo-controlled trial, the Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD; n = 89). Measurements and Main Results The 200 genes most differentially expressed in asthma versus healthy control subjects were enriched among genes associated with more severe airflow obstruction in these COPD cohorts (P < 0.001), suggesting significant gene expression overlap. A higher T2S score was associated with decreased lung function (P < 0.001), but not asthma history, in both COPD cohorts. Higher T2S scores correlated with increased airway wall eosinophil counts (P = 0.003), blood eosinophil percentage (P = 0.03), bronchodilator reversibility (P = 0.01), and improvement in hyperinflation after corticosteroid treatment (P = 0.019) in GLUCOLD. Conclusions These data identify airway gene expression alterations that can co-occur in asthma and COPD. The association of the T2S score with increased severity and “asthma-like” features (including a favorable corticosteroid response) in COPD suggests that Th2 inflammation is important in a COPD subset that cannot be identified by clinical history of asthma.

Accurate prediction of an individual’s phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. We extend a powerful individual-level data Bayesian multiple regression model (BayesR) to one that utilises summary statistics from genome-wide association studies (GWAS), SBayesR. In simulation and cross-validation using 12 real traits and 1.1 million variants on 350,000 individuals from the UK Biobank, SBayesR improves prediction accuracy relative to commonly used state-of-the-art summary statistics methods at a fraction of the computational resources. Furthermore, using summary statistics for variants from the largest GWAS meta-analysis ( n ≈ 700, 000) on height and BMI, we show that on average across traits and two independent data sets that SBayesR improves prediction R 2 by 5.2% relative to LDpred and by 26.5% relative to clumping and p  value thresholding. Various approaches are being used for polygenic prediction including Bayesian multiple regression methods that require access to individual-level genotype data. Here, the authors extend BayesR to utilise GWAS summary statistics (SBayesR) and show that it outperforms other summary statistic-based methods.

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Patients with asthma vary markedly in their clinical response to inhaled glucocorticoids. These investigators used a novel approach to identify a common variant in the glucocorticoid-induced transcript 1 gene associated with a decreased response to glucocorticoids. Asthma is a complex genetic syndrome that affects 300 million persons worldwide. 1 The response to treatment is also genetically complex and is characterized by high intraindividual repeatability 2 and high interindividual variability, 3 with up to 40% of patients with asthma having no response to therapy. Inhaled glucocorticoids are the most widely prescribed medications for controlling asthma. Levels of endogenous glucocorticoids are heritable and vary, both at baseline and in response to environmental perturbation. 4 – 6 Moreover, studies in families with conditions other than asthma have shown both familial segregation and heritability in responses to glucocorticoid medications. 7 , 8 Given the heritability within the . . .

Self-reported race or ethnic group is used to determine reference standards in the prediction of lung function. This study suggests that the inclusion of genetic measures of African ancestry may improve predictions of lung function. Studies investigating the clinical usefulness of genetic markers of ancestry in determining the severity of pulmonary disease seem to be warranted. The use of racial or ethnic classification in medical practice and research has been the subject of debate. 1 – 3 Race and ethnicity are complex constructs incorporating social, cultural, and genetic factors. Currently, pulmonary-function testing is one of the few clinical applications in which self-reported race or ethnic group is used to define a normal range for a test outcome. Normative equations of lung function have been developed by testing large populations categorized on the basis of self-reported race or ethnic group. 4 However, many populations are racially admixed, and self-identified racial and ethnic categories are crude descriptors of individual genetic ancestry. . . .

Background Chronic obstructive pulmonary disease (COPD) is characterized by progressive lung function decline, commonly measured by forced expiratory volume in one second (FEV 1 ). Uncovering the genetic basis of FEV 1 decline is essential for understanding COPD pathophysiology and for developing therapies. We hypothesized that gene expression patterns in inflammatory pathways are associated with FEV 1 decline. Methods We analyzed whole blood RNA-sequencing data from the 5 ( n  = 4,147) and 10 year visits ( n  = 435) in the COPDGene Study. Gene expression was assessed in three analyses: cross-sectional associations with FEV 1 at two separate time points, association between year 5 gene expression and FEV 1 changes from year 5–10, and longitudinal changes in both gene expression and FEV 1 . A gene signature derived from the 5-year visit was linked to FEV 1 decline across three intervals (baseline to 5 years, 5 to 10 years, and baseline to 10 years) and tested for validation in the ECLIPSE study. Results Distinct gene sets emerged in the three analyses (Cross-sectional: 961 genes; FEV 1 Change: 179; Longitudinal: 532). Only two genes ( NOV and AC009404.2 ) overlapped across all analyses, while unique genes (e.g., MMP9 , IL1RL1 , and CHI3L1 ) were context-specific. Pathway analysis of genes from the longitudinal analysis highlighted oxidative stress and immune processes. A 20-gene signature was derived, including 17 genes positively and three negatively associated with FEV 1 . These signatures were significantly associated with FEV 1 -related traits in COPDGene and ECLIPSE. Conclusions These findings reveal molecular markers of FEV 1 decline, offering insights into COPD pathophysiology and potential therapeutic targets.

A variant of MMP12, encoding a matrix metallopeptidase, is associated with increased lung function in children with asthma and in adult smokers. It is also associated with a decreased risk of chronic obstructive pulmonary disease in adult smokers. A variant of MMP12 is associated with increased lung function in children with asthma and in adult smokers. It is also associated with a decreased risk of chronic obstructive pulmonary disease in adult smokers. MMP-12 (matrix metalloproteinase 12, also known as macrophage metalloelastase or matrix metallopeptidase 12 [Mmp12] in mice) is produced by macrophages, the predominant cell type that patrols the lower airspaces under normal conditions and the main inflammatory cell type that is recruited with smoking. 1 Mmp12 is essential for the development of emphysema in mice exposed to cigarette smoke, 2 including mice with increased expression of interleukin-13. 3 Increased expression of MMP12 in the lower airways can lead to degradation of elastin, resulting in elastin fragments that can cause a positive feedback loop, further increasing macrophage recruitment in mice 4 and in cultured human cells. . . .

Abstract Rationale Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

BackgroundThe association between lower adult lung function and increased cardiovascular comorbidity has not been adequately explained. We investigated whether shared developmental signalling pathways, critical to lung development and repair, could partly explain it.MethodsIn UK Biobank (UKB), we performed pairwise colocalisation analysis of variants in 55 lung development genes associated with adult forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1)/FVC, to see if these are also associated with coronary heart disease (CHD), blood pressure (systolic, diastolic, hypertension), pulse pressure, Arterial Stiffness index and carotid intima-media thickness. For CHD, we meta-analysed data from UKB and the CARDIoGRAM consortium.ResultsWe found that 12 of the 55 genes shared the same variant between one (or more) lung function trait and one (or more) cardiovascular trait (H4colocalisation). The direction of effects was always in keeping with our hypothesis (lower lung function–higher cardiovascular risk) for FVC, but not always for FEV1/FVC. The seven signals for hypertension and CHD all replicated nominally in the FinnGen study, while replication was poor in the China Kadoorie Biobank (CKB) study. In addition, we found a further 10 genes where genetic associations with lung function and cardiovascular traits were within the same gene but involved different variants (H3 colocalisation). Interestingly, six of all 22 genes (H4 and H3 colocalisation) were novel for cardiovascular traits; four replicated in FinnGen, three in CKB.ConclusionLung function and cardiovascular traits have shared developmental pathways that may partly explain why lower lung function, especially FVC, is associated with increased cardiovascular risk.