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FastSKAT: Sequence kernel association tests for very large sets of markers.
Wednesday,2019-01-09 13:03 America/Los_Angeles — ecterry
| Title | FastSKAT: Sequence kernel association tests for very large sets of markers. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | Lumley, T, Brody, J, Peloso, G, Morrison, A, Rice, K |
| Journal | Genet Epidemiol |
| Volume | 42 |
| Issue | 6 |
| Pagination | 516-527 |
| Date Published | 2018 09 |
| ISSN | 1098-2272 |
| Keywords | Algorithms, Chromosomes, Human, Genetic Association Studies, Genetic Markers, Histones, Humans, Sequence Analysis, DNA, Statistics as Topic, Time Factors |
| Abstract | <p>The sequence kernel association test (SKAT) is widely used to test for associations between a phenotype and a set of genetic variants that are usually rare. Evaluating tail probabilities or quantiles of the null distribution for SKAT requires computing the eigenvalues of a matrix related to the genotype covariance between markers. Extracting the full set of eigenvalues of this matrix (an <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>n</mml:mi><mml:mo>×</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:math> matrix, for n subjects) has computational complexity proportional to n . As SKAT is often used when <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>n</mml:mi><mml:mo></mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mn>4</mml:mn></mml:msup></mml:mrow></mml:math> , this step becomes a major bottleneck in its use in practice. We therefore propose fastSKAT, a new computationally inexpensive but accurate approximations to the tail probabilities, in which the k largest eigenvalues of a weighted genotype covariance matrix or the largest singular values of a weighted genotype matrix are extracted, and a single term based on the Satterthwaite approximation is used for the remaining eigenvalues. While the method is not particularly sensitive to the choice of k, we also describe how to choose its value, and show how fastSKAT can automatically alert users to the rare cases where the choice may affect results. As well as providing faster implementation of SKAT, the new method also enables entirely new applications of SKAT that were not possible before; we give examples grouping variants by topologically associating domains, and comparing chromosome-wide association by class of histone marker.</p> |
| DOI | 10.1002/gepi.22136 |
| Alternate Journal | Genet. Epidemiol. |
| PubMed ID | 29932245 |
| PubMed Central ID | PMC6129408 |
| Grant List | RC2 HL102419 / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States U01HL137162 / HL / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201700001I / HL / NHLBI NIH HHS / United States R01AG023629 / AG / NIA NIH HHS / United States HHSN268201700004I / HL / NHLBI NIH HHS / United States U01 HL137162 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States HHSN268201700002I / HL / NHLBI NIH HHS / United States HHSN268201700005I / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States HHSN268201700003I / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States N02 HL64278 / HL / NHLBI NIH HHS / United States |
ePub date:
18/09