Abstract
Rheumatoid arthritis (RA) has an estimated heritability of nearly 50%, which is particularly high in seropositive RA. HLA alleles account for a large proportion of this heritability, in addition to many common single-nucleotide polymorphisms with smaller individual effects. Low-frequency and rare variants, such as those captured by next-generation sequencing, can also have a large role in heritability in some individuals. Rare variant discovery has informed the development of drugs such as inhibitors of PCSK9 and Janus kinases. Some 34 low-frequency and rare variants are currently associated with RA risk. One variant (19:10352442G>C in TYK2) was identified in five separate studies, and might therefore represent a promising therapeutic target. Following a set of best practices in future studies, including studying diverse populations, using large sample sizes, validating RA and serostatus, replicating findings, adjusting for other variants and performing functional assessment, could help to ensure the relevance of identified variants. Exciting opportunities are now on the horizon for genetics in RA, including larger datasets and consortia, whole-genome sequencing and direct applications of findings in the management, and especially treatment, of RA.
Key points
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The greatest contributors to RA heritability are the major histocompatibility complex (MHC) proteins, encoded by the human leukocyte antigen (HLA) region on chromosome 6.
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Low-frequency and rare variants captured by next-generation sequencing can have large effects on both individual-level heritability and population-level drug discovery.
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Thus far, 34 low-frequency and rare variants have been associated with RA, including variants in immune-related genes such as TYK2 that might represent therapeutic targets.
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Best practice for identifying rare variants in RA includes studying diverse populations, including ≥3,000 affected individuals, validating RA, examining serostatus, replicating findings, adjusting for known variants and performing functional assessment.
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Acknowledgements
This manuscript was supported by the Rheumatology Research Foundation Scientist Development Award (V.L.K.).
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V.L.K., J.A.S. & J.R.C. researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.
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Related links
ABC: https://github.com/broadinstitute/ABC-Enhancer-Gene-Prediction
ANNOVAR: https://annovar.openbioinformatics.org/en/latest/user-guide/download/
CADD: https://cadd.gs.washington.edu/
CAVA: https://www.rdm.ox.ac.uk/research/lunter-group/lunter-group/cava-clinical-annotation-of-variants
gnomAD: https://gnomad.broadinstitute.org/
GTEx: https://gtexportal.org/home/
MetaDome: https://stuart.radboudumc.nl/metadome/
Polyphen-2: http://genetics.bwh.harvard.edu/pph2/
ProteinPaint: https://proteinpaint.stjude.org/
REVEL: https://sites.google.com/site/revelgenomics/about
SCENT: https://github.com/immunogenomics/SCENT
SIFT: https://sift.bii.a-star.edu.sg/
Single-Nucleotide Polymorphism database: https://www.ncbi.nlm.nih.gov/snp/
Glossary
- Allele
-
One of two or more alternative forms at the same location of a gene or intergenic region.
- Common variants
-
Genetic variants with a minor allele frequency >5%.
- Copy number variation
-
Variation owing to insertions and deletions of sequences >1,000 base pairs, with copies at least 90% identical.
- Exome
-
The small fraction of the genome (1% in humans) that directly encodes proteins.
- Functional annotation
-
The process of attaching biological information to genetic variants.
- Gene-based tests
-
A statistical approach to genetic analysis that conserves power by combining both the strength and the number of multiple variant associations into one test.
- Genome
-
The complete set of genetic material in any organism.
- Genome-wide association study
-
A study to determine the association of genetic variants throughout the genome with phenotypic traits.
- Germline variants
-
Variants in germ-cell DNA that are inherited at conception.
- Heritability
-
The proportion of a phenotype attributable to genetic factors.
- Indel
-
Insertion or deletion of base pairs from a genetic sequence.
- Low-frequency variants
-
Genetic variants with minor-allele frequency 1–5%.
- Minor allele frequency
-
The frequency of the second most common allele in a given population.
- Missing heritability
-
The gap between predicted and observed heritability, which is observed across many phenotypes.
- Next-generation sequencing
-
(also known as massive parallel sequencing). A group of technologies for DNA sequencing that sequence many reads in parallel.
- Phenome-wide association study
-
A study design for examination of the association between a variant of interest and a large number of phenotypes.
- Phenotype
-
An observable trait that is influenced by genetics and environment.
- Rare variants
-
Genetic variants with minor-allele frequency <1%.
- Sanger sequencing
-
Also known as ‘first-generation sequencing’. A method of DNA sequencing that uses chain-terminating dideoxyneucleotides to produce labelled fragments corresponding to a DNA template.
- Single-nucleotide polymorphism
-
(SNP). A genetic substitution at a single base pair that occurs in at least 1% of the population.
- Single-nucleotide variant
-
(SNV). A genetic substitution at a single base pair.
- Somatic variants
-
Variants that occur in DNA after conception.
- Structural variation
-
Large-scale genomic variation, usually involving >50 base pairs.
- Targeted sequencing
-
DNA sequencing targeting only specific genes.
- Transcriptome
-
The set of all RNA transcripts generated from the genome.
- Ultra-rare variants
-
Genetic variants with very low minor-allele frequency, often defined as <0.1%.
- Whole-exome sequencing
-
DNA sequencing of the full exome.
- Whole-genome sequencing
-
DNA sequencing of the full genome.
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Kronzer, V.L., Sparks, J.A., Raychaudhuri, S. et al. Low-frequency and rare genetic variants associated with rheumatoid arthritis risk. Nat Rev Rheumatol 20, 290–300 (2024). https://doi.org/10.1038/s41584-024-01096-7
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DOI: https://doi.org/10.1038/s41584-024-01096-7