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Genetic Variations in Olfactory Receptor Gene OR2AG2 in a Large www.nature.com/scientificreports OPEN Genetic variations in olfactory receptor gene OR2AG2 in a large multigenerational family with asthma Samarpana Chakraborty1,2, Pushkar Dakle1, Anirban Sinha 1, Sangeetha Vishweswaraiah3, Aditya Nagori1,2, Shivalingaswamy Salimath4, Y. S. Prakash5, R. Lodha6, S. K. Kabra6, Balaram Ghosh1,2, Mohammed Faruq1,2, P. A. Mahesh4 & Anurag Agrawal1,2* It is estimated from twin studies that heritable factors account for at-least half of asthma-risk, of which genetic variants identifed through population studies explain only a small fraction. Multi-generation large families with high asthma prevalence can serve as a model to identify highly penetrant genetic variants in closely related individuals that are missed by population studies. To achieve this, a four- generation Indian family with asthma was identifed and recruited for examination and genetic testing. Twenty subjects representing all generations were selected for whole genome genotyping, of which eight were subjected to exome sequencing. Non-synonymous and deleterious variants, segregating with the afected individuals, were identifed by exome sequencing. A prioritized deleterious missense common variant in the olfactory receptor gene OR2AG2 that segregated with a risk haplotype in asthma, was validated in an asthma cohort of diferent ethnicity. Phenotypic tests were conducted to verify expected defcits in terms of reduced ability to sense odors. Pathway-level relevance to asthma biology was tested in model systems and unrelated human lung samples. Our study suggests that OR2AG2 and other olfactory receptors may contribute to asthma pathophysiology. Genetic studies on large families of interest can lead to efcient discovery. Asthma is a chronic disorder of the airways caused by a strong genetic predisposition, in addition to environmen- tal insults1. Previous genetic studies in asthma such as linkage analysis, twin studies, candidate gene approaches and GWAS (Genome Wide Association Studies), have identifed numerous candidate genes and variants for asthma, but all the associated variants can explain less than 15% of the genetic risk2. Tus, a large piece of the puzzle is missing. Te gap may be reduced by gaining information of genetic variants that are missed by the pop- ulation studies, but may have strong efects in closely related individuals that share the variants. Discovery of such highly penetrant variants associated with asthma-risk is more efcient through the study of closely related indi- viduals, such as multi-generation large families, rather than population based studies. Next generation sequenc- ing has shown a promise in identifying novel targets which were previously missed by the candidate gene based approaches3. Exome sequencing i.e. sequencing the coding regions of the genome in a familial set up has proven to be highly informative in the context of other complex diseases such as cardiovascular diseases and Alzheimer’s disease4,5 Earlier, in Indian population, using candidate gene and genome wide candidate gene approaches, several genes including those for cytokines, FcεR1, STAT6 and INPP4A were found to be associated with asthma6,7. In India, there exists a rich reservoir of large families owing to endogamy and the concept of compound families. Also, cases of consanguinity and inter-clan marriages provide an excellent ground for well-designed genetic stud- ies. Since asthma is a complex and heterogeneous disorder, we hypothesized that a study design that can enable 1Centre of Excellence for Translational Research in Asthma and Lung Diseases, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India. 2Academy of Scientifc and Innovative Research (AcSIR), Chennai, India. 3Genetics and Genomics Lab, Department of Genetics and Genomics, University of Mysore, Manasagangotri, Mysuru, Karnataka, India. 4Department of Pulmonary Medicine, JSS Medical College, JSSAHER, Mysore, Karnataka, India. 5Departments of Anesthesiology, Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA. 6Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. *email: [email protected] SCIENTIFIC REPORTS | (2019) 9:19029 | https://doi.org/10.1038/s41598-019-54718-6 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Figure 1. Pedigree and sample information of family 1. Family 1 is a four generation family with approximately 40% individuals afected with asthma and atopy. Samples collected are marked with * symbol. Black square/ circle denotes afected members while clear square/circle denotes unafected subjects. No clear inheritance pattern could be identifed from the pedigree. Interestingly, this family also has cases of consanguinity (depicted by double-lines=). Eight subjects- II:5, III:7, III:9, III:10, IV:31, IV:34, V:27, V:42 (fve cases and three controls) were selected for Exome Sequencing. identifcation of highly penetrating genetic variants could be achieved by studying large families with multiple generations afected with asthma. For this, a subset of subjects belonging to a four generation family from south- ern India with clinical history of asthma and atopy over four generations were selected for exome sequencing. In addition to this, all available samples from the family were subjected to whole genome genotyping for linkage and haplotype analysis. Post bioinformatics analysis of exome sequencing and sequencing validation, a genetic variant from one can- didate gene OR2AG2, encoding an olfactory receptor, was found in our multi-generational family to be novel in asthma. Literature suggests the expression of olfactory receptors on the airways similar to bitter taste receptors, and having roles in mucociliary clearance on activating stimuli by strong odor8. Studies in recent past, including a GWAS in a Korean population reported signifcant importance of olfactory receptors with respect to lung func- tion9. We hypothesized that defect in sensing and clearance by these receptors may trigger exacerbations, which is a commonly observed phenomenon in asthmatics in presence of strong/volatile odor. Olfactory receptors having a pertinent role in the human lungs is a relatively new concept. We, therefore, explored the putative role of olfac- tory receptor gene, OR2AG2 in the context of allergic asthma using in vitro systems and human lung samples. Results Exome sequencing and analysis pipeline. A four generation pedigree was constructed with information provided by the family (Fig. 1). Clinical details of participating subjects are provided in Table 1. Eight samples were subjected to exome sequencing using the Illumina platform. A couple with consanguinity along with a distant member of the family were chosen for sequencing since their shared genome will be less, thus providing higher chances of fnding variants that truly segregate with the disease. Data obtained afer sequencing was subjected to an analysis pipeline (Supplementary Fig. E1A). Te average coverage of sequencing was ≈50X. A total of 115463 variants were identifed, post annotation. We aimed at identifying variants that segregated with only afected subjects and were absent in unafected subjects. For this, a model free approach was used, since asthma is a complex disease and the pedigree showed a multifarious mode of disease inheritance. 910 variants were seen to segregate with the afected members of the family. Tese variants were further subjected to prioritization, before technical validation. Variant prioritization strategies. To understand the possible implication of all the identifed segregat- ing variants, the following parameters were used: 1. In-silico prediction tools (explained in Supplementary and SCIENTIFIC REPORTS | (2019) 9:19029 | https://doi.org/10.1038/s41598-019-54718-6 2 www.nature.com/scientificreports/ www.nature.com/scientificreports Asthma Control Age (Mean Year ± SEM) 50 ± 5.2 45.16 ± 6.6 Gender (M/F) (9/5) (3/3) Weight (kg) (Mean ± SEM) 67 ± 4.2 62.3 ± 7.4 No. of Smokers 2 2 Pre-BD Post-BD Pre-BD Post-BD Mean FEV1(L) 1.63 1.77 1.76 1.82 Mean FVC (L) 2.23 2.34 2.01 2.19 Mean FEV1/FVC 0.7 0.72 0.82 0.82 Mean zFEV1 −3.74 −3.55 −3.41 −3.12 % BDR_FEV1 7.90 3.40 % BDR_FVC 4.93 8.95 Table 1. Clinical details of subjects participating in the study from family 1. Pre/post BD: Pre/post bronchodilation, FEV1 : Forced expiratory volume in one second, FVC : Forced vital capacity, % BDR : Percent bronchodilator responsiveness. Te spirometry data has been analysed using lung function equations for Indian population34. Figure 2. List of variants for validation of Family 1. Te fgure shows the list of novel variants (lef) that were subjected to validation in additional members from family 1 to flter out false positives from exome sequencing, using Sanger (in italics) and SNaPshot sequencing reactions, (MAF: Minor allele frequency). Te list of validated variants is shown in right. Supplementary Fig. E1B) were exploited to understand the possible implication of the variants in human physi- ology and disease, and the ones predicted to have damaging consequences were considered. 2. Genetic variants from genes unreported in asthma (novel) that co-segregated with the disease were given priority. Te idea to focus on these variants was in concordance with our initial hypothesis that a fraction of missing heritability for asthma is attributable to deleterious and highly penetrating genetic variants that are more likely to be identifed in a large family based set-up. In-silico predicted deleterious variants
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