Document Detail

Rare and low-frequency variants in human common diseases and other complex traits.
MedLine Citation:
PMID:  25185437     Owner:  NLM     Status:  Publisher    
In humans, most of the genetic variation is rare and often population-specific. Whereas the role of rare genetic variants in familial monogenic diseases is firmly established, we are only now starting to explore the contribution of this class of genetic variation to human common diseases and other complex traits. Such large-scale experiments are possible due to the development of next-generation DNA sequencing. Early findings suggested that rare and low-frequency coding variation might have a large effect on human phenotypes (eg, PCSK9 missense variants on low-density lipoprotein-cholesterol and coronary heart diseases). This observation sparked excitement in prognostic and diagnostic medicine, as well as in genetics-driven strategies to develop new drugs. In this review, I describe results and present initial conclusions regarding some of the recent rare and low-frequency variant discoveries. We can already assume that most phenotype-associated rare and low-frequency variants have modest-to-weak phenotypical effect. Thus, we will need large cohorts to identify them, as for common variants in genome-wide association studies. As we expand the list of associated rare and low-frequency variants, we can also better recognise the current limitations: we need to develop better statistical methods to optimally test association with rare variants, including non-coding variation, and to account for potential confounders such as population stratification.
Guillaume Lettre
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Publication Detail:
Type:  REVIEW     Date:  2014-9-3
Journal Detail:
Title:  Journal of medical genetics     Volume:  -     ISSN:  1468-6244     ISO Abbreviation:  J. Med. Genet.     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-9-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985087R     Medline TA:  J Med Genet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
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