NDLI: Nanopore sequencing as a novel method of characterising anorexia nervosa risk loci

Content Provider	Springer Nature : BioMed Central
Author	Berthold, Natasha Gaudieri, Silvana Hood, Sean Tschochner, Monika Miller, Allison L. Jordan, Jennifer Thornton, Laura M. Bulik, Cynthia M. Akkari, Patrick Anthony Kennedy, Martin A.
Abstract	Background Anorexia nervosa (AN) is a polygenic, severe metabopsychiatric disorder with poorly understood aetiology. Eight significant loci have been identified by genome-wide association studies (GWAS) and single nucleotide polymorphism (SNP)-based heritability was estimated to be ~ 11–17, yet causal variants remain elusive. It is therefore important to define the full spectrum of genetic variants in the wider regions surrounding these significantly associated loci. The hypothesis we evaluate here is that unrecognised or relatively unexplored variants in these regions exist and are promising targets for future functional analyses. To test this hypothesis, we implemented a novel approach with targeted nanopore sequencing (Oxford Nanopore Technologies) for 200 kb regions centred on each of the eight AN-associated loci in 10 AN case samples. Our bioinformatics pipeline entailed base-calling and alignment with Dorado and minimap2 software, followed by variant calling with four separate tools, Sniffles2, Clair3, Straglr, and NanoVar. We then leveraged publicly available databases to characterise these loci in putative functional context and prioritise a subset of potentially relevant variants. Results Targeted nanopore sequencing effectively enriched the target regions (average coverage 14.64x). To test our hypothesis, we curated a list of 20 prioritised variants in non-coding regions, poorly represented in the current human reference genome but that may have functional consequences in AN pathology. Notably, we identified a polymorphic SINE-VNTR-Alu like sub-family D element (SVA-D), intergenic with IP6K2 and PRKAR2A, and a poly-T short tandem repeat (STR) in the 3ʹUTR of FOXP1. Conclusions Our results highlight the potential of targeted nanopore sequencing for characterising poorly resolved or complex variation, which may be initially obscured in risk-associated regions detected by GWAS. Some of the variants identified in this way, such as the polymorphic SVA-D and poly-T STR, could contribute to mechanisms of phenotypic risk, through regulation of several neighbouring genes implicated in AN biology, and affect post-transcriptional processing of FOXP1, respectively. This exploratory investigation was not powered to detect functional effects, however, the variants we observed using this method are poorly represented in the current human reference genome and accompanying databases, and further examination of these may provide new opportunities for improved understanding of genetic risk mechanisms of AN.
Related Links	https://bmcgenomics.biomedcentral.com/counter/pdf/10.1186/s12864-024-11172-7.pdf
Ending Page	11
Page Count	11
Starting Page	1
File Format	HTM / HTML
ISSN	14712164
DOI	10.1186/s12864-024-11172-7
Journal	BMC Genomics
Issue Number	1
Volume Number	25
Language	English
Publisher	BioMed Central
Publisher Date	2024-12-31
Access Restriction	Open
Subject Keyword	Life Sciences Microarrays Proteomics Animal Genetics and Genomics Microbial Genetics and Genomics Plant Genetics and Genomics Eating disorders Psychiatric genetics Anorexia nervosa risk loci Structural variants Transposable elements Nanopore sequencing Long-read sequencing Adaptive sampling Targeted sequencing
Content Type	Text
Resource Type	Article
Subject	Biotechnology Genetics
Journal Impact Factor	3.5/2023
5-Year Journal Impact Factor	4.1/2023

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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