Abstract:

Recent progress in biological clock research has facilitated genetic analysis of circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24). We analyzed the human period3 (hPer3) gene, one of the human homologs of the Drosophila clock-gene period (Per), as a possible candidate for rhythm disorder susceptibility. All of the coding exons in the hPer3 gene were screened for polymorphisms by a PCR-based strategy using genomic DNA samples from sleep disorder patients and control subjects. We identified six sequence variations with amino acid changes, of which five were common and predicted four haplotypes of the hPer3 gene. One of the haplotypes was significantly associated with DSPS (Bonferroni's corrected P = 0.037; odds ratio = 7.79; 95% CI 1.59-38.3) in our study population. Our results suggest that structural polymorphisms in the hPer3 gene may be implicated in the pathogenesis of DSPS.

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Association of structural polymorphisms in the human <em>period3</em> gene with delayed sleep phase syndrome

K Shibui+14 authors

^{Department of Psychiatry, Saitama Medical School, 38 Morohongo, Saitama 350-0495,}

^{Department of Psychophysiology, National Center of Neurology and Psychiatry (NCNP), 1-7-3 Kohnodai, Chiba 272-0827,}

^{Musashi Hospital, NCNP, 4-1-1 Ogawa-cho, Tokyo 187-0031,}

^{Department of Psychiatry, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543,}

^{Kohnodai Hospital, NCNP, 1-7-1 Kohnodai, Chiba 272-0827,}

^{Department of Psychiatry, Tokyo Women’s Medical College, 8-1 Kawata-cho, Tokyo 162-8666,}

^{Department of Psychiatry, Shiga University of Medical Science, Seta Tsukinowa-cho, Shiga 520-2192,}

^{Department of Psychiatry, Juntendo University, School of Medicine, 2-1-1 Hongo, Tokyo 113-8431,}

^{Kazusa DNA Research Institute, 1532-3 Yana, Chiba 292-0812,}

^{Department of Psychiatry, Fujita Health University School of Medicine, Machida Rakugabuchi, Aichi 470-1192 and}

^{National Institute of Bioscience and Human Technology, Agency of Industrial Science and Technology, 1-1 Higashi, Ibaraki 305-8566, Japan}

^{Corresponding author. Tel: +81 492 76 1213; Fax: +81 492 76 1622; E-mail:}p j.ca.dem-amatias@awasibet

Received 2000 Nov 23; Revised 2001 Feb 12; Accepted 2001 Feb 12.

Abstract

Recent progress in biological clock research has facilitated genetic analysis of circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep–wake syndrome (N-24). We analyzed the human period3 (hPer3) gene, one of the human homologs of the Drosophila clock-gene period (Per), as a possible candidate for rhythm disorder susceptibility. All of the coding exons in the hPer3 gene were screened for polymorphisms by a PCR-based strategy using genomic DNA samples from sleep disorder patients and control subjects. We identified six sequence variations with amino acid changes, of which five were common and predicted four haplotypes of the hPer3 gene. One of the haplotypes was significantly associated with DSPS (Bonferroni’s corrected P = 0.037; odds ratio = 7.79; 95% CI 1.59–38.3) in our study population. Our results suggest that structural polymorphisms in the hPer3 gene may be implicated in the pathogenesis of DSPS.

Abstract

In parentheses are the nucleotide positions in the sequence of accession No. {"type":"entrez-nucleotide","attrs":{"text":"Z98884","term_id":"5304861","term_text":"Z98884"}}Z98884.

To avoid complications, nucleotide and amino acid positions are numbered according to the full-length hPer3 cDNA sequence containing five copies of a 54 bp repeat ({"type":"entrez-nucleotide","attrs":{"text":"AB047686","term_id":"13160924","term_text":"AB047686"}}AB047686). The 3110(T→C) [M1037T] and the 3473(A→G)[H1158R] polymorphisms are estimated to be exclusively on a 4-repeat allele; therefore, actual nucleotide (nt) and amino acid (aa) positions relative to the putative initiation site are 3056 nt (1019 aa) and 3419 nt (1141 aa), respectively.

Underlined are minor alleles in each polymorphic locus.

Statistical comparisons were performed using a two-tailed Fisher’s exact test.

^P = 0.0055 versus controls, Bonferroni’s corrected P = 0.033.

^P = 0.0062 versus controls, odds ratio = 7.79, 95% CI 1.59–38.3, Bonferroni’s corrected P = 0.037.

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ACKNOWLEDGEMENTS

Technical contributions by Eiichi Yamada, Kyoko Ohnishi and Masakazu Kinoshita are gratefully acknowledged. This work was supported by research grants from the Ministry of Health and Welfare, and the Ministry of Education, Science, Sports, and Culture (10557089, 11233206, 12470198) and Saitama Medical School.

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