Vol. 72, No. 4, 2011
Issue release date: December 2011
Free Access
Hum Hered 2011;72:228–236
(DOI:10.1159/000334381)
Paper
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Linkage Analysis in the Next-Generation Sequencing Era

Bailey-Wilson J.E. · Wilson A.F.
Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Md., USA
email Corresponding Author


 goto top of outline Key Words

  • Linkage
  • Genetics
  • DNA sequence
  • Whole-genome sequence
  • Whole-exome sequence

 goto top of outline Abstract

Linkage analysis was developed to detect excess co-segregation of the putative alleles underlying a phenotype with the alleles at a marker locus in family data. Many different variations of this analysis and corresponding study design have been developed to detect this co-segregation. Linkage studies have been shown to have high power to detect loci that have alleles (or variants) with a large effect size, i.e. alleles that make large contributions to the risk of a disease or to the variation of a quantitative trait. However, alleles with a large effect size tend to be rare in the population. In contrast, association studies are designed to have high power to detect common alleles which tend to have a small effect size for most diseases or traits. Although genome-wide association studies have been successful in detecting many new loci with common alleles of small effect for many complex traits, these common variants often do not explain a large proportion of disease risk or variation of the trait. In the past, linkage studies were successful in detecting regions of the genome that were likely to harbor rare variants with large effect for many simple Mendelian diseases and for many complex traits. However, identifying the actual sequence variant(s) responsible for these linkage signals was challenging because of difficulties in sequencing the large regions implicated by each linkage peak. Current ‘next-generation’ DNA sequencing techniques have made it economically feasible to sequence all exons or the whole genomes of a reasonably large number of individuals. Studies have shown that rare variants are quite common in the general population, and it is now possible to combine these new DNA sequencing methods with linkage studies to identify rare causal variants with a large effect size. A brief review of linkage methods is presented here with examples of their relevance and usefulness for the interpretation of whole-exome and whole-genome sequence data.

Copyright © 2011 S. Karger AG, Basel


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 goto top of outline Author Contacts

Joan E. Bailey-Wilson, PhD
NIH/NHGRI
333 Cassell Drive, Suite 1200
Baltimore, MD 21224 (USA)
Tel. +1 443 740 2921, E-Mail jebw@mail.nih.gov


 goto top of outline Article Information

Published online: December 23, 2011
Number of Print Pages : 9
Number of Figures : 0, Number of Tables : 0, Number of References : 154


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 72, No. 4, Year 2011 (Cover Date: December 2011)

Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


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