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Genetic variants associated with sleep disorders.

Kripke DF, Kline LE, Nievergelt CM, Murray SS, Shadan FF, Dawson A, Poceta JS, Cronin J, Jamil SM, Tranah GJ, Loving RT, Grizas AP, Hahn EK - Sleep Med. (2014)

Bottom Line: In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration.SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep.SNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. Electronic address: dkripke1@san.rr.com.

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Quantile–quantile plot of P values. The ranked P values of SNP associations with sleep phenotypes are plotted with x symbols for 23,294 P values. The values above the Bonferroni-corrected criteria for P < 0.05 (thick dashed line) were approximately one log unit above the random expectations (i.e., P values ~0.10 times random expectations). Only the single association for rs4964515 in CRY1 with the questionnaire-reported weekday time of falling asleep was substantially above the random trend (P = 1.99E10–7).
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Figure 1: Quantile–quantile plot of P values. The ranked P values of SNP associations with sleep phenotypes are plotted with x symbols for 23,294 P values. The values above the Bonferroni-corrected criteria for P < 0.05 (thick dashed line) were approximately one log unit above the random expectations (i.e., P values ~0.10 times random expectations). Only the single association for rs4964515 in CRY1 with the questionnaire-reported weekday time of falling asleep was substantially above the random trend (P = 1.99E10–7).

Mentions: The reliability of 13 Bonferroni-significant associations among regressions with a total of 38 phenotypes is difficult to appraise, considering that various SNPs were genetically linked and various phenotypes were intercorrelated. An overall perspective was offered by q false-discovery statistics, which estimate the chances of a false-positive discovery among multiple comparisons [43]. The overall q statistics were computed by compiling the P values for all of the SNP regressions for all phenotypes in combination, a total of 23,294 P estimates. The false-discovery estimates were as follows: for rs4964515 in CRY1, P = 1.99E-07 and q = 0.0045. For P values of 8.28E-06 to 1.09E-05, the risk of false discovery was estimated as q = 0.062. For P values of 2.62E-05 to 7.82E-05, q was estimated as 0.107–0.125. In other words, the Bonferroni-significant P values ranging from 8.28E-06 to 7.82E-05 had chances of roughly 6–13% of representing false discoveries. For P values of 0.000107–0.000895, q was estimated as 0.161–0.495. These estimates indicate that P values exceeding 0.000934 were >50% likely to be false discoveries, for example, a nominal P > 0.0208 was about 90% likely to be a false discovery. A graphic perspective is presented by Fig. 1, a quantile–quantile plot of the same 23,294 P values, which shows the observed P values below the Bonferroni criteria to be rather close to the random expectation. The Bonferroni-significant values were somewhat above expectation, but only the observed P value near 10−7 was impressively above the random expectation illustrated in the Q–Q plot.


Genetic variants associated with sleep disorders.

Kripke DF, Kline LE, Nievergelt CM, Murray SS, Shadan FF, Dawson A, Poceta JS, Cronin J, Jamil SM, Tranah GJ, Loving RT, Grizas AP, Hahn EK - Sleep Med. (2014)

Quantile–quantile plot of P values. The ranked P values of SNP associations with sleep phenotypes are plotted with x symbols for 23,294 P values. The values above the Bonferroni-corrected criteria for P < 0.05 (thick dashed line) were approximately one log unit above the random expectations (i.e., P values ~0.10 times random expectations). Only the single association for rs4964515 in CRY1 with the questionnaire-reported weekday time of falling asleep was substantially above the random trend (P = 1.99E10–7).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352103&req=5

Figure 1: Quantile–quantile plot of P values. The ranked P values of SNP associations with sleep phenotypes are plotted with x symbols for 23,294 P values. The values above the Bonferroni-corrected criteria for P < 0.05 (thick dashed line) were approximately one log unit above the random expectations (i.e., P values ~0.10 times random expectations). Only the single association for rs4964515 in CRY1 with the questionnaire-reported weekday time of falling asleep was substantially above the random trend (P = 1.99E10–7).
Mentions: The reliability of 13 Bonferroni-significant associations among regressions with a total of 38 phenotypes is difficult to appraise, considering that various SNPs were genetically linked and various phenotypes were intercorrelated. An overall perspective was offered by q false-discovery statistics, which estimate the chances of a false-positive discovery among multiple comparisons [43]. The overall q statistics were computed by compiling the P values for all of the SNP regressions for all phenotypes in combination, a total of 23,294 P estimates. The false-discovery estimates were as follows: for rs4964515 in CRY1, P = 1.99E-07 and q = 0.0045. For P values of 8.28E-06 to 1.09E-05, the risk of false discovery was estimated as q = 0.062. For P values of 2.62E-05 to 7.82E-05, q was estimated as 0.107–0.125. In other words, the Bonferroni-significant P values ranging from 8.28E-06 to 7.82E-05 had chances of roughly 6–13% of representing false discoveries. For P values of 0.000107–0.000895, q was estimated as 0.161–0.495. These estimates indicate that P values exceeding 0.000934 were >50% likely to be false discoveries, for example, a nominal P > 0.0208 was about 90% likely to be a false discovery. A graphic perspective is presented by Fig. 1, a quantile–quantile plot of the same 23,294 P values, which shows the observed P values below the Bonferroni criteria to be rather close to the random expectation. The Bonferroni-significant values were somewhat above expectation, but only the observed P value near 10−7 was impressively above the random expectation illustrated in the Q–Q plot.

Bottom Line: In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration.SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep.SNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. Electronic address: dkripke1@san.rr.com.

Show MeSH
Related in: MedlinePlus