title: Old lessons learned anew: family-based methods for detecting genes responsible for quantitative and qualitative traits in the Genetic Analysis Workshop 17 mini-exome sequence data.
abstract: Family-based study designs are again becoming popular as new next-generation sequencing technologies make whole-exome and whole-genome sequencing projects economically and temporally feasible. Here we evaluate the statistical properties of linkage analyses and family-based tests of association for the Genetic Analysis Workshop 17 mini-exome sequence data. Based on our results, the linkage methods using relative pairs or nuclear families had low power, with the best results coming from variance components linkage analysis in nuclear families and Elston-Stewart model-based linkage analysis in extended pedigrees. For family-based tests of association, both ASSOC and ROMP performed well for genes with large effects, but ROMP had the advantage of not requiring parental genotypes in the analysis. For the linkage analyses we conclude that genome-wide significance levels appear to control type I error well but that "suggestive" significance levels do not. Methods that make use of the extended pedigrees are well powered to detect major loci segregating in the families even when there is substantial genetic heterogeneity and the trait is mainly polygenic. However, large numbers of such pedigrees will be necessary to detect all major loci. The family-based tests of association found the same major loci as the linkage analyses and detected low-frequency loci with moderate effect sizes, but control of type I error was not as stringent.
authors.affiliation: Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Simpson
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Justice
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Mera
authors.initials: M
authors.lastname: Krishnan
authors.affiliation: Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wojciechowski
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Heejong
authors.initials: H
authors.lastname: Sung
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Cai
authors.affiliation: Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Green
authors.affiliation: Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Deyana
authors.initials: D
authors.lastname: Lewis
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Behneman
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
authors.affiliation: Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Drive, 333 Cassell Drive Suite 1200, Baltimore, MD 21224, USA.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson