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. 2021 Dec 14;19(1):183.
doi: 10.1186/s43141-021-00268-2.

Genetic epidemiology of autoinflammatory disease variants in Indian population from 1029 whole genomes

Abhinav Jain  1   2 , Rahul C Bhoyar  1 , Kavita Pandhare  1 , Anushree Mishra  1 , Disha Sharma  1 , Mohamed Imran  1   2 , Vigneshwar Senthivel  1   2 , Mohit Kumar Divakar  1   2 , Mercy Rophina  1   2 , Bani Jolly  1   2 , Arushi Batra  1   2 , Sumit Sharma  1 , Sanjay Siwach  1 , Arun G Jadhao  3 , Nikhil V Palande  4 , Ganga Nath Jha  5 , Nishat Ashrafi  5 , Prashant Kumar Mishra  6 , Vidhya A K  7 , Suman Jain  8 , Debasis Dash  1   2 , Nachimuthu Senthil Kumar  9 , Andrew Vanlallawma  9 , Ranjan Jyoti Sarma  9 , Lalchhandama Chhakchhuak  10 , Shantaraman Kalyanaraman  11 , Radha Mahadevan  11 , Sunitha Kandasamy  11 , Pabitha B M  11 , Raskin Erusan Rajagopal  11 , Ezhil Ramya J  11 , Nirmala Devi P  11 , Anjali Bajaj  1   2 , Vishu Gupta  1   2 , Samatha Mathew  1   2 , Sangam Goswami  1   2 , Mohit Mangla  1   2 , Savinitha Prakash  1 , Kandarp Joshi  1 , Meyakumla  1 , Sreedevi S  12 , Devarshi Gajjar  13 , Ronibala Soraisham  14 , Rohit Yadav  1   2 , Yumnam Silla Devi  15 , Aayush Gupta  16 , Mitali Mukerji  1   2 , Sivaprakash Ramalingam  1   2 , Binukumar B K  1   2 , Vinod Scaria  17   18 , Sridhar Sivasubbu  19   20
Affiliations

Genetic epidemiology of autoinflammatory disease variants in Indian population from 1029 whole genomes

Abhinav Jain et al. J Genet Eng Biotechnol. .

Abstract

Background: Autoinflammatory disorders are the group of inherited inflammatory disorders caused due to the genetic defect in the genes that regulates innate immune systems. These have been clinically characterized based on the duration and occurrence of unprovoked fever, skin rash, and patient's ancestry. There are several autoinflammatory disorders that are found to be prevalent in a specific population and whose disease genetic epidemiology within the population has been well understood. However, India has a limited number of genetic studies reported for autoinflammatory disorders till date. The whole genome sequencing and analysis of 1029 Indian individuals performed under the IndiGen project persuaded us to perform the genetic epidemiology of the autoinflammatory disorders in India.

Results: We have systematically annotated the genetic variants of 56 genes implicated in autoinflammatory disorder. These genetic variants were reclassified into five categories (i.e., pathogenic, likely pathogenic, benign, likely benign, and variant of uncertain significance (VUS)) according to the American College of Medical Genetics and Association of Molecular pathology (ACMG-AMP) guidelines. Our analysis revealed 20 pathogenic and likely pathogenic variants with significant differences in the allele frequency compared with the global population. We also found six causal founder variants in the IndiGen dataset belonging to different ancestry. We have performed haplotype prediction analysis for founder mutations haplotype that reveals the admixture of the South Asian population with other populations. The cumulative carrier frequency of the autoinflammatory disorder in India was found to be 3.5% which is much higher than reported.

Conclusion: With such frequency in the Indian population, there is a great need for awareness among clinicians as well as the general public regarding the autoinflammatory disorder. To the best of our knowledge, this is the first and most comprehensive population scale genetic epidemiological study being reported from India.

Keywords: Allele frequency; American College of Medical Genetics and Genomics; Autoinflammatory disorder; Genetic epidemiology; Haplotype ancestry.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic summarizing the data analysis pipeline utilized in this study
Fig. 2
Fig. 2
Variant filtering and classification based on ACMG-AMP guidelines. A Variant prioritization for ACMG classification. B Variant classification based on ACMG-AMP guidelines. C Pathogenic and likely pathogenic variants classification based on the type of variant
Fig. 3
Fig. 3
Comparison of allele frequency of pathogenic and likely pathogenic variants in the IndiGen population with the gnomAD, 1000 genome project (1KG), Esp6500, Greater Middle East (GME), and Qatar (Q) and its subpopulation: Amish (AMI), European (Finnish) (EUR (Fin)),, European (Non Finnish) (EUR (Non Fin)), African (AFR), Ashkenazi Jewish (ASJ), East Asian (EAS), South Asian (SAS), American (AMR), Bedouin (BED), Sub-Saharan African (SAF), European (EUR), South Asian (SOU), African Pygmy (APY), Arab (ARA), Persian (PER), Northwest Africa (NWA), Northeast Africa (NEA), Turkish Peninsula (TP), Syrian Desert (SD), Arabian Peninsula (AP), and Persia and Pakistan (PP). CA, Central Asia. Significant allele frequency highlighted with the red circle
Fig. 4
Fig. 4
Visualization of haplotype ancestry of founder variants in IndiGen individuals with 5MB upstream and downstream mapped to the five superpopulation of 1000 Genome Project A) The chromosomal painting of Georgian Jewish founder variant rs202134424-T (marked with red arrow) in four IndiGen individuals. B) The chromosomal painting of East Asian founder variant rs148755083 (marked with red arrow) in two IndiGen individuals. C) The chromosomal painting of Georgian Jewish founder variant rs202134424-G found in a single IndiGen individual. D) The chromosomal painting of Asian founder variant rs78635798 (marked with red arrow) in a single IndiGen individual. E) The chromosomal painting of Dutch population founder variant rs28934897 in seven IndiGen individuals. AFR Africa, AMR America, EAS East Asia, EUR European, SAS South Asian
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