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A rare variant is a genetic variant which occurs at low frequency in a population.^[1] Rare variants play a significant role in both complex and Mendelian disease and are responsible for a portion of the missing heritability of complex diseases. The theoretical case for a significant role of rare variants is that alleles that strongly predispose an individual to disease will be kept at low frequencies in populations by purifying selection.^[2] Rare variants are increasingly being studied, as a consequence of whole exome and whole genome sequencing efforts. While these variants are individually infrequent in populations, there are many in human populations, and they can be unique to specific populations. They are more likely to be deleterious than common variants, as a result of rapid population growth and weak purifying selection.^[3] They have been suspected of acting independently or along with common variants to cause disease states.^[4]

Methods of discovery

Some methods, such as genetic burden tests, have been specifically developed to study genetic association of rare variants.^[5] These methods aggregate rare variants over genetic regions, such as genes or whole pathways, and evaluate cumulative effects of multiple genetic variants. These methods may increase power when multiple variants in the region are associated with a disease or a trait. In addition, compared to a genome-wide association study, a region or gene based test performs much fewer tests resulting in a less stringent multiple-hypothesis correction than the genome-wide significance.^[6] Some examples of these methods are SKAT,^[7] SKAT-O,^[5] ARIEL test,^[8] aSUM^[9] and STAAR.^[10] SNP annotations help to prioritize rare functional variants, and incorporating these annotations can effectively boost the power of genetic association of rare variants analysis of whole exome and whole genome sequencing studies.^[11] ^[12]

References

^ Erjavec SO, Gelfman S, Abdelaziz AR, Lee EY, Monga I, Alkelai A, Ionita-Laza I, Petukhova L, Christiano AM (Feb 2022). "Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82". Nat Commun. 13 (1): 800. Bibcode:2022NatCo..13..800E. doi:10.1038/s41467-022-28343-3. PMC 8831607. PMID 35145093.
^ Goldstein, DB; Allen, A; Keebler, J; Margulies, EH; Petrou, S; Petrovski, S; Sunyaev, S (July 2013). "Sequencing studies in human genetics: design and interpretation". Nature Reviews Genetics. 14 (7): 460–70. doi:10.1038/nrg3455. PMC 4117319. PMID 23752795.
^ Nelson, M. R.; Wegmann, D.; Ehm, M. G.; Kessner, D.; St. Jean, P.; Verzilli, C.; Shen, J.; Tang, Z.; Bacanu, S.-A.; Fraser, D.; Warren, L.; Aponte, J.; Zawistowski, M.; Liu, X.; Zhang, H.; Zhang, Y.; Li, J.; Li, Y.; Li, L.; Woollard, P.; Topp, S.; Hall, M. D.; Nangle, K.; Wang, J.; Abecasis, G.; Cardon, L. R.; Zollner, S.; Whittaker, J. C.; Chissoe, S. L.; Novembre, J.; Mooser, V. (17 May 2012). "An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People". Science. 337 (6090): 100–104. Bibcode:2012Sci...337..100N. doi:10.1126/science.1217876. PMC 4319976. PMID 22604722.
^ Panoutsopoulou, K.; Tachmazidou, I.; Zeggini, E. (6 August 2013). "In search of low-frequency and rare variants affecting complex traits". Human Molecular Genetics. 22 (R1): R16 – R21. doi:10.1093/hmg/ddt376. PMC 3782074. PMID 23922232.
^ ^a ^b Lee, Seunggeun; Emond, Mary J.; Bamshad, Michael J.; Barnes, Kathleen C.; Rieder, Mark J.; Nickerson, Deborah A.; Christiani, David C.; Wurfel, Mark M.; Lin, Xihong (August 2012). "Optimal Unified Approach for Rare-Variant Association Testing with Application to Small-Sample Case-Control Whole-Exome Sequencing Studies". The American Journal of Human Genetics. 91 (2): 224–237. doi:10.1016/j.ajhg.2012.06.007. ISSN 0002-9297. PMC 3415556. PMID 22863193.
^ Lee, Seunggeung; Abecasis, Gonçalo R.; Boehnke, Michael; Lin, Xihong (July 2014). "Rare-Variant Association Analysis: Study Designs and Statistical Tests". The American Journal of Human Genetics. 95 (1): 5–23. doi:10.1016/j.ajhg.2014.06.009. ISSN 0002-9297. PMC 4085641. PMID 24995866.
^ Wu, Michael C.; Lee, Seunggeun; Cai, Tianxi; Li, Yun; Boehnke, Michael; Lin, Xihong (July 2011). "Rare-Variant Association Testing for Sequencing Data with the Sequence Kernel Association Test". The American Journal of Human Genetics. 89 (1): 82–93. doi:10.1016/j.ajhg.2011.05.029. ISSN 0002-9297. PMC 3135811. PMID 21737059.
^ Asimit, Jennifer L.; Day-Williams, Aaron G.; Morris, Andrew P.; Zeggini, Eleftheria (2012). "ARIEL and AMELIA: testing for an accumulation of rare variants using next-generation sequencing data". Human Heredity. 73 (2): 84–94. doi:10.1159/000336982. ISSN 1423-0062. PMC 3477640. PMID 22441326.
^ Han, Fang; Pan, Wei (June 2010). "A Data-Adaptive Sum Test for Disease Association with Multiple Common or Rare Variants". Human Heredity. 70 (1): 42–54. doi:10.1159/000288704. ISSN 0001-5652. PMC 2912645. PMID 20413981.
^ Li, Xihao; Li, Zilin; Zhou, Hufeng; Gaynor, Sheila M.; Liu, Yaowu; Chen, Han; Sun, Ryan; Dey, Rounak; Arnett, Donna K.; Aslibekyan, Stella; Ballantyne, Christie M.; Bielak, Lawrence F.; Blangero, John; Boerwinkle, Eric; Bowden, Donald W.; Broome, Jai G; Conomos, Matthew P; Correa, Adolfo; Cupples, L. Adrienne; Curran, Joanne E.; Freedman, Barry I.; Guo, Xiuqing; Hindy, George; Irvin, Marguerite R.; Kardia, Sharon L. R.; Kathiresan, Sekar; Khan, Alyna T.; Kooperberg, Charles L.; Laurie, Cathy C.; Liu, X. Shirley; Mahaney, Michael C.; Manichaiku, Ani W.; Martin, Lisa W.; Mathias, Rasika A.; McGarvey, Stephen T.; Mitchell, Braxton D.; Montasser, May E.; Moore, Jill E.; Morrison3, Alanna C.; O’Connell, Jeffrey R.; Palmer, Nicholette D.; Pampana, Akhil; Peralta, Juan M.; Peyser, Patricia A.; Psaty, Bruce M.; Redline, Susan; Rice, Kenneth M.; Rich, Stephen S.; Smith, Jennifer A.; Tiwari, Hemant K.; Tsai, Michael Y.; Vasan, Ramachandran S.; Wang, Fei Fei; Weeks, Daniel E.; Weng, Zhiping; Wilson, James G.; Yanek, Lisa R.; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Lipids Working Group; Neale, Benjamin M.; Sunyaev, Shamil R.; Abecasis, Gonçalo R.; Rotter, Jerome I.; Willer, Cristen J.; Peloso, Gina M.; Natarajan, Pradeep; Lin, Xihong (Sep 2020). "Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale". Nature Genetics. 52 (9): 969–983. doi:10.1038/s41588-020-0676-4. ISSN 1061-4036. PMC 7483769. PMID 32839606.{{cite journal}}: CS1 maint: numeric names: authors list (link)
^ Li, Zilin; Li, Xihao; Zhou, Hufeng; Gaynor, Sheila M.; Margaret, Sunitha Selvaraj; Arapoglou, Theodore; Qiuck, Corbin; Liu, Yaowu; Chen, Han; Sun, Ryan; Dey, Rounak; Arnett, Donna K.; Auer, Paul L.; Bielak, Lawrence F.; Bis, Joshua C.; Blackwell, Thomas W.; Blangero, John; Boerwinkle, Eric; Bowden, Donald W.; Brody, Jennifer A.; Cade, Brian E.; Conomos, Matthew P.; Correa, Adolfo; Cupples, L. Adrienne; Curran, Joanne E.; de Vries, Paul S.; Duggirala, Ravindranath; Franceschini, Nora; Freedman, Barry I.; Goring, Harald H.H.; Guo, Xiuqing; Kalyani, Rita R.; Kooperberg, Charles; Kral, Brian G.; Lange, Leslie A.; Lin, Bridget; Manichaikul, Ani; Martin, Lisa W.; Mathias, Rasika A.; Meigs, James B.; Mitchell, Braxton D.; Mitchell, Braxton D.; Montasser, May E.; Morrison, Alanna C.; Naseri, Take; O’Connell, Jeffrey R.; Palmer, Nicholette D.; Reupena, Muagututi’a Sefuiva; Rice, Kenneth M.; Rich, Stephen S.; Smith, Jennifer A.; Taylor, Kent D.; Taub, Margaret A.; Vasan, Ramachandran S.; Weeks, Daniel E.; Wilson, James G.; Yanek, Lisa R.; Zhao, Wei; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Lipids Working Group; Rotter, Jerome I.; Willer, Cristen; Natarajan, Pradeep; Peloso, Gina M.; Lin, Xihong (2022). "A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies". Nature Methods. 19 (12): 1599–1611. doi:10.1038/s41592-022-01640-x. PMC 10008172. PMID 36303018. S2CID 243873361.
^ Li, Xihao; Quick, Corbin; Zhou, Hufeng; Gaynor, Sheila M.; Liu, Yaowu; Chen, Han; Selvaraj, Margaret Sunitha; Sun, Ryan; Dey, Rounak; Arnett, Donna K.; Bielak, Lawrence F.; Bis, Joshua C.; Blangero, John; Boerwinkle, Eric; Bowden, Donald W.; Brody, Jennifer A.; Cade, Brian E.; Correa, Adolfo; Cupples, L. Adrienne; Curran, Joanne E.; de Vries, Paul S.; Duggirala, Ravindranath; Freedman, Barry I.; Göring, Harald H. H.; Guo, Xiuqing; Haessler, Jeffrey; Kalyani, Rita R.; Kooperberg, Charles; Kral, Brian G.; Lange, Leslie A.; Manichaikul, Ani; Martin, Lisa W.; McGarvey, Stephen T.; Mitchell, Braxton D.; Montasser, May E.; Morrison, Alanna C.; Naseri, Take; O’Connell, Jeffrey R.; Palmer, Nicholette D.; Peyser, Patricia A.; Psaty, Bruce M.; Raffield, Laura M.; Redline, Susan; Reiner, Alexander P.; Reupena, Muagututi’a Sefuiva; Rice, Kenneth M.; Rich, Stephen S.; Sitlani, Colleen M.; Smith, Jennifer A.; Taylor, Kent D.; Vasan, Ramachandran S.; Willer, Cristen J.; Wilson, James G.; Yanek, Lisa R.; Zhao, Wei; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Lipids Working Group; Rotter, Jerome I.; Natarajan, Pradeep; Peloso, Gina M.; Li, Zilin; Lin, Xihong (January 2023). "Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies". Nature Genetics. 55 (1): 154–164. doi:10.1038/s41588-022-01225-6. PMC 10084891.

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Rare variant (genetics)

Methods of discovery

See also

References

Further reading

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