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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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CRY1 rs4964515 versus subjective time when falling asleep. Questionnaire-reported time to fall asleep (ordinate) is plotted against the rs4964515 AG genotype (group at left) and the GG genotype (group at right), both groups spread out for better visualization. Although the median time of reported falling asleep was certainly later for the AG genotype with one rare allele, the linear regression P = 2.0E-07 value was strongly influenced by one outlying point. The Mann–Whitney rank-order contrast of the two groups was significant only at the P = 0.0001 level, which would not meet Bonferroni criteria.
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Figure 5: CRY1 rs4964515 versus subjective time when falling asleep. Questionnaire-reported time to fall asleep (ordinate) is plotted against the rs4964515 AG genotype (group at left) and the GG genotype (group at right), both groups spread out for better visualization. Although the median time of reported falling asleep was certainly later for the AG genotype with one rare allele, the linear regression P = 2.0E-07 value was strongly influenced by one outlying point. The Mann–Whitney rank-order contrast of the two groups was significant only at the P = 0.0001 level, which would not meet Bonferroni criteria.

Mentions: Two other SNPs related to phenotypes of disturbed sleep were CSNK1D rs11552085 and CRY1 rs4964515. Both were nominally associated with reduced subjectively reported total sleep time, with subjective insomnia, and with later reported clock times to fall asleep both on weekdays and on weekends. In CSNK1D, heterozygotes (N = 8) with the minor allele of rs11552085 were associated with 3.37 times the polysomnographic sleep latency (Bonferroni P < 0.02), but the five participants of non-European ancestry with one or two minor alleles did not have longer sleep latencies. For CRY1 rs4964515, the Bonferroni P = 1.99E-07 for reported time falling asleep was the smallest P value obtained in all the analyses, and as mentioned above, this was the only association with a false-discovery probability of q = 0.0045, suggesting statistical reliability. As shown in Fig. 5, this highly significant contrast was derived largely from one outlying participant’s very late reported time of falling asleep on weekdays (among only 11 with the minor allele), as the reported time of falling asleep on weekends was several orders of magnitude less significant, and the polysomnographic sleep latency was not associated with CRY1 SNPs at all. The Mann–Whitney rank-order contrast of the two groups was significant only at the P = 0.0001 level. Moreover, our sample of non-European ancestry had included 23 participants with an rs4964515 minor allele, and the minor allele had no significant association with any phenotype. No indication of a similar association of rs4964515 with delayed falling asleep was found in our companion sample of DSPS cases and controls [37]. For these reasons, despite the very small estimated q value, we must be quite skeptical that this rs4964515 association was a true positive until replicated, and the same is true of the rs11552085 findings. It is notable that neither rs11552085 nor rs4964515 showed evidence of DSPS on the BALM scale, so the meaning of a delayed sleep onset would be uncertain.


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)

CRY1 rs4964515 versus subjective time when falling asleep. Questionnaire-reported time to fall asleep (ordinate) is plotted against the rs4964515 AG genotype (group at left) and the GG genotype (group at right), both groups spread out for better visualization. Although the median time of reported falling asleep was certainly later for the AG genotype with one rare allele, the linear regression P = 2.0E-07 value was strongly influenced by one outlying point. The Mann–Whitney rank-order contrast of the two groups was significant only at the P = 0.0001 level, which would not meet Bonferroni criteria.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: CRY1 rs4964515 versus subjective time when falling asleep. Questionnaire-reported time to fall asleep (ordinate) is plotted against the rs4964515 AG genotype (group at left) and the GG genotype (group at right), both groups spread out for better visualization. Although the median time of reported falling asleep was certainly later for the AG genotype with one rare allele, the linear regression P = 2.0E-07 value was strongly influenced by one outlying point. The Mann–Whitney rank-order contrast of the two groups was significant only at the P = 0.0001 level, which would not meet Bonferroni criteria.
Mentions: Two other SNPs related to phenotypes of disturbed sleep were CSNK1D rs11552085 and CRY1 rs4964515. Both were nominally associated with reduced subjectively reported total sleep time, with subjective insomnia, and with later reported clock times to fall asleep both on weekdays and on weekends. In CSNK1D, heterozygotes (N = 8) with the minor allele of rs11552085 were associated with 3.37 times the polysomnographic sleep latency (Bonferroni P < 0.02), but the five participants of non-European ancestry with one or two minor alleles did not have longer sleep latencies. For CRY1 rs4964515, the Bonferroni P = 1.99E-07 for reported time falling asleep was the smallest P value obtained in all the analyses, and as mentioned above, this was the only association with a false-discovery probability of q = 0.0045, suggesting statistical reliability. As shown in Fig. 5, this highly significant contrast was derived largely from one outlying participant’s very late reported time of falling asleep on weekdays (among only 11 with the minor allele), as the reported time of falling asleep on weekends was several orders of magnitude less significant, and the polysomnographic sleep latency was not associated with CRY1 SNPs at all. The Mann–Whitney rank-order contrast of the two groups was significant only at the P = 0.0001 level. Moreover, our sample of non-European ancestry had included 23 participants with an rs4964515 minor allele, and the minor allele had no significant association with any phenotype. No indication of a similar association of rs4964515 with delayed falling asleep was found in our companion sample of DSPS cases and controls [37]. For these reasons, despite the very small estimated q value, we must be quite skeptical that this rs4964515 association was a true positive until replicated, and the same is true of the rs11552085 findings. It is notable that neither rs11552085 nor rs4964515 showed evidence of DSPS on the BALM scale, so the meaning of a delayed sleep onset would be uncertain.

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