A coalescent simulation of marker selection strategy for candidate gene association studies.

@article{citeulike:1838492, abstract = {Recent efforts have focused on the challenges of finding alleles that contribute to health-related phenotypes in genome-wide association studies. However, in candidate gene studies, where the genomic region of interest is small and recombination is limited, factors that affect the ability to detect disease-susceptibility alleles remain poorly understood. In particular, it is unclear how varying the number of markers on a haplotype, the type of marker (e.g., single nucleotide polymorphism (SNP), short tandem repeat (STR)), including the causative site (cs) as a genetic marker, or population demographics influences the power to detect a candidate gene. We evaluated the power of association tests using coalescent-modeled computer simulations. Results show that an effective number of markers on a haplotype is dependent on whether the cs is included as a marker. When the analyses include the cs, highest power is achieved with a single-marker association test. However, when the cs is excluded from analyses, the addition of more nonfunctional SNPs on the haplotype increases power to a certain point under most scenarios. We find a rapidly expanding population always has lower power compared to a population of constant size; although utilizing markers with a frequency of at least 5\% improves the chance of detecting an association. Comparing the mutational properties of a nonfunctional SNP versus an STR, multi-allelic STRs provide more or comparable power than a bi-allelic SNP unless SNP frequencies are constrained to 10\% or more. Similarly, including an STR with SNPs on a haplotype improves power unless SNP frequencies are 5\% or more. (c) 2007 Wiley-Liss, Inc.}, address = {Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.}, author = {Cole, Suzanne M M. and Long, Jeffrey C C. }, citeulike-article-id = {1838492}, doi = {10.1002/ajmg.b.30564}, issn = {1552-4841}, journal = {Am J Med Genet B Neuropsychiatr Genet}, month = {August}, posted-at = {2007-10-30 03:03:34}, priority = {2}, title = {A coalescent simulation of marker selection strategy for candidate gene association studies.}, url = {http://dx.doi.org/10.1002/ajmg.b.30564}, year = {2007} }

TY - JOUR ID - citeulike:1838492 L3 - citeulike-article-id:1838492 TI - A coalescent simulation of marker selection strategy for candidate gene association studies. JF - Am J Med Genet B Neuropsychiatr Genet AD - Department of Human Genetics, University of Michigan, Ann Arbor, Michigan. SN - 1552-4841 N2 - Recent efforts have focused on the challenges of finding alleles that contribute to health-related phenotypes in genome-wide association studies. However, in candidate gene studies, where the genomic region of interest is small and recombination is limited, factors that affect the ability to detect disease-susceptibility alleles remain poorly understood. In particular, it is unclear how varying the number of markers on a haplotype, the type of marker (e.g., single nucleotide polymorphism (SNP), short tandem repeat (STR)), including the causative site (cs) as a genetic marker, or population demographics influences the power to detect a candidate gene. We evaluated the power of association tests using coalescent-modeled computer simulations. Results show that an effective number of markers on a haplotype is dependent on whether the cs is included as a marker. When the analyses include the cs, highest power is achieved with a single-marker association test. However, when the cs is excluded from analyses, the addition of more nonfunctional SNPs on the haplotype increases power to a certain point under most scenarios. We find a rapidly expanding population always has lower power compared to a population of constant size; although utilizing markers with a frequency of at least 5% improves the chance of detecting an association. Comparing the mutational properties of a nonfunctional SNP versus an STR, multi-allelic STRs provide more or comparable power than a bi-allelic SNP unless SNP frequencies are constrained to 10% or more. Similarly, including an STR with SNPs on a haplotype improves power unless SNP frequencies are 5% or more. (c) 2007 Wiley-Liss, Inc. AU - Cole, Suzanne M AU - Long, Jeffrey C PY - 2007/08/22/ UR - http://dx.doi.org/10.1002/ajmg.b.30564 ER -