TY - JOUR
T1 - Rare-variant extensions of the transmission disequilibrium test
T2 - Application to autism exome sequence data
AU - He, Zongxiao
AU - O'Roak, Brian J.
AU - Smith, Joshua D.
AU - Wang, Gao
AU - Hooker, Stanley
AU - Santos-Cortez, Regie Lyn P.
AU - Li, Biao
AU - Kan, Mengyuan
AU - Krumm, Nik
AU - Nickerson, Deborah A.
AU - Shendure, Jay
AU - Eichler, Evan E.
AU - Leal, Suzanne M.
N1 - Funding Information:
We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, E. Hanson, D. Grice, A. Klin, R. Kochel, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. This work was supported by the Simons Foundation Autism Research Initiative (SFARI 137578 and 191889 to E.E.E. and J.S.). E.E.E. is an Investigator of the Howard Hughes Medical Institute. This study was also funded by the National Institutes of Health grants HD065285, HL102926, MD005964, and HG006493.
PY - 2014/1/2
Y1 - 2014/1/2
N2 - Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.
AB - Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.
UR - http://www.scopus.com/inward/record.url?scp=84891831893&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891831893&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2013.11.021
DO - 10.1016/j.ajhg.2013.11.021
M3 - Article
C2 - 24360806
AN - SCOPUS:84891831893
SN - 0002-9297
VL - 94
SP - 33
EP - 46
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -