Rare variant (genetics)

A '''rare variant''' is a genetic variant which occurs at low frequency in a population.<ref name="Erjavec">{{cite journal | vauthors = Erjavec SO, Gelfman S, Abdelaziz AR, Lee EY, Monga I, Alkelai A, Ionita-Laza I, Petukhova L, Christiano AM| title = Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82| journal = Nat Commun | volume = 13 | issue = 1| pages = 800 | date = Feb 2022 | pmid = 35145093 | doi = 10.1038/s41467-022-28343-3| pmc = 8831607| bibcode = 2022NatCo..13..800E}}</ref> 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.<ref>{{cite journal|last1=Goldstein|first1=DB|last2=Allen|first2=A|last3=Keebler|first3=J|last4=Margulies|first4=EH|last5=Petrou|first5=S|last6=Petrovski|first6=S|last7=Sunyaev|first7=S|title=Sequencing studies in human genetics: design and interpretation.|journal=Nature Reviews Genetics|date=July 2013|volume=14|issue=7|pages=460–70|pmid=23752795|doi=10.1038/nrg3455|pmc=4117319}}</ref> 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.<ref name=Nelson>{{cite journal|last1=Nelson|first1=M. R.|last2=Wegmann|first2=D.|last3=Ehm|first3=M. G.|last4=Kessner|first4=D.|last5=St. Jean|first5=P.|last6=Verzilli|first6=C.|last7=Shen|first7=J.|last8=Tang|first8=Z.|last9=Bacanu|first9=S.-A.|last10=Fraser|first10=D.|last11=Warren|first11=L.|last12=Aponte|first12=J.|last13=Zawistowski|first13=M.|last14=Liu|first14=X.|last15=Zhang|first15=H.|last16=Zhang|first16=Y.|last17=Li|first17=J.|last18=Li|first18=Y.|last19=Li|first19=L.|last20=Woollard|first20=P.|last21=Topp|first21=S.|last22=Hall|first22=M. D.|last23=Nangle|first23=K.|last24=Wang|first24=J.|last25=Abecasis|first25=G.|last26=Cardon|first26=L. R.|last27=Zollner|first27=S.|last28=Whittaker|first28=J. C.|last29=Chissoe|first29=S. L.|last30=Novembre|first30=J.|last31=Mooser|first31=V.|title=An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People|volume=337|issue=6090|journal=Science|pages=100–104|doi=10.1126/science.1217876|pmid=22604722|pmc=4319976|date=17 May 2012|bibcode=2012Sci...337..100N}}</ref> They have been suspected of acting independently or along with common variants to cause disease states.<ref name=Panoutsopoulou>{{cite journal|last1=Panoutsopoulou|first1=K.|last2=Tachmazidou|first2=I.|last3=Zeggini|first3=E.|author-link3=Eleftheria Zeggini|title=In search of low-frequency and rare variants affecting complex traits|pmc=3782074|journal=Human Molecular Genetics|volume=22|issue=R1|pages=R16–R21|doi=10.1093/hmg/ddt376|pmid=23922232|date=6 August 2013}}</ref>

== Methods of discovery == Some methods, such as genetic burden tests, have been specifically developed to study genetic association of rare variants.<ref name=":0">{{Cite journal|last1=Lee|first1=Seunggeun|last2=Emond|first2=Mary J.|last3=Bamshad|first3=Michael J.|last4=Barnes|first4=Kathleen C.|last5=Rieder|first5=Mark J.|last6=Nickerson|first6=Deborah A.|last7=Christiani|first7=David C.|last8=Wurfel|first8=Mark M.|last9=Lin|first9=Xihong|date=August 2012|title=Optimal Unified Approach for Rare-Variant Association Testing with Application to Small-Sample Case-Control Whole-Exome Sequencing Studies|url= |journal=The American Journal of Human Genetics|volume=91|issue=2|pages=224–237|doi=10.1016/j.ajhg.2012.06.007|issn=0002-9297|pmc=3415556|pmid=22863193}}</ref> 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.<ref>{{Cite journal|last1=Lee|first1=Seunggeung|last2=Abecasis|first2=Gonçalo R.|last3=Boehnke|first3=Michael|last4=Lin|first4=Xihong|date=July 2014|title=Rare-Variant Association Analysis: Study Designs and Statistical Tests|url= |journal=The American Journal of Human Genetics|volume=95|issue=1|pages=5–23|doi=10.1016/j.ajhg.2014.06.009|issn=0002-9297|pmc=4085641|pmid=24995866}}</ref> Some examples of these methods are SKAT,<ref>{{Cite journal|last1=Wu|first1=Michael C.|last2=Lee|first2=Seunggeun|last3=Cai|first3=Tianxi|last4=Li|first4=Yun|last5=Boehnke|first5=Michael|last6=Lin|first6=Xihong|date=July 2011|title=Rare-Variant Association Testing for Sequencing Data with the Sequence Kernel Association Test|url= |journal=The American Journal of Human Genetics|volume=89|issue=1|pages=82–93|doi=10.1016/j.ajhg.2011.05.029|pmid=21737059|pmc=3135811|issn=0002-9297}}</ref> SKAT-O,<ref name=":0" /> ARIEL test,<ref>{{Cite journal|last1=Asimit|first1=Jennifer L.|last2=Day-Williams|first2=Aaron G.|last3=Morris|first3=Andrew P.|last4=Zeggini|first4=Eleftheria|date=2012|title=ARIEL and AMELIA: testing for an accumulation of rare variants using next-generation sequencing data|journal=Human Heredity|volume=73|issue=2|pages=84–94|doi=10.1159/000336982|issn=1423-0062|pmc=3477640|pmid=22441326}}</ref> aSUM<ref>{{Cite journal|last1=Han|first1=Fang|last2=Pan|first2=Wei|date=June 2010|title=A Data-Adaptive Sum Test for Disease Association with Multiple Common or Rare Variants|journal=Human Heredity|volume=70|issue=1|pages=42–54|doi=10.1159/000288704|issn=0001-5652|pmc=2912645|pmid=20413981}}</ref> and STAAR.<ref name=":1">{{Cite journal|last1=Li|first1=Xihao|last2=Li|first2=Zilin|last3=Zhou|first3=Hufeng|last4=Gaynor|first4=Sheila M.|last5=Liu|first5=Yaowu|last6=Chen|first6=Han|last7=Sun|first7=Ryan|last8=Dey|first8=Rounak|last9=Arnett|first9=Donna K.|last10=Aslibekyan|first10=Stella|last11=Ballantyne|first11=Christie M.|last12=Bielak|first12=Lawrence F.|last13=Blangero|first13=John|last14=Boerwinkle|first14=Eric|last15=Bowden|first15=Donald W.|last16=Broome|first16=Jai G|last17=Conomos|first17=Matthew P| last18=Correa|first18=Adolfo|last19=Cupples|first19=L. 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==References== {{reflist}}

==Further reading== *[http://www.nature.com/nature/journal/v498/n7453/fig_tab/nature12170_F1.html Association analyses of discovered rare functional variants in autoimmune diseases] *[https://www.nature.com/articles/s41588-020-0676-4 Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale] *[https://www.nature.com/articles/s41592-022-01641-w STAARpipeline: an all-in-one rare-variant tool for biobank-scale whole-genome sequencing data] *[https://www.nature.com/articles/4001728 Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive compulsive disorder] Category:Human genetics Category:Genetic diseases and disorders Category:Long stubs with short prose