No simple answer to complex disease

Access through your institution Buy or subscribe Mutations that underlie Mendelian diseases are generally single-nucleotide changes that have a strong effect on protein function, consistent

with the fact that these diseases involve single mutations with strong phenotypic effects. Complex diseases, on the other hand, are caused by multiple mutations, implying that each mutation

has a weak effect on its own. This has led to the suggestion that SNPs that are associated with complex disorders are more likely to have milder effects on protein function or to affect

regulatory non-coding regions. However, several studies of complex disease have identified SNPs in coding regions as having causal roles, indicating that their molecular basis might be

similar to Mendelian disorders after all. To test these possibilities, the authors examined SNPs identified from previous studies as being associated with complex disease and looked at how

likely they are to have severe effects on protein function. They did this by determining how conserved the amino acids affected are in related proteins from different species — highly

conserved positions are likely to have essential roles in protein function. Positions affected in complex disease turn out to be far less conserved than for Mendelian disorders, with a

distribution similar to genetic variation in healthy individuals. So, unlike Mendelian disorders, polymorphisms that underlie complex genetic disease probably have small effects on protein

function. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online

access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which

are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support ORIGINAL RESEARCH PAPER * Thomas, P.

D. & Kejariwal, A. Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. _Proc. Natl Acad.

Sci. USA_ 18 October 2004 (doi:10.1073/pnas.0404380101) Download references Authors * Louisa Flintoft View author publications You can also search for this author inPubMed Google Scholar

RELATED LINKS RELATED LINKS WEB SITE Paul Thomas's laboratory RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Flintoft, L. No simple answer to

complex disease. _Nat Rev Genet_ 5, 886–887 (2004). https://doi.org/10.1038/nrg1497 Download citation * Issue Date: 01 December 2004 * DOI: https://doi.org/10.1038/nrg1497 SHARE THIS ARTICLE

Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative