Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes (original) (raw)

Nature Genetics volume 27, pages 435–438 (2001)Cite this article

Abstract

Most human sequence variation is in the form of single-nucleotide polymorphisms1,2,3 (SNPs). It has been proposed that coding-region SNPs (cSNPs) be used for direct association studies to determine the genetic basis of complex traits4,5. The success of such studies depends on the frequency of disease-associated alleles, and their distribution in different ethnic populations6,7. If disease-associated alleles are frequent in most populations, then direct genotyping of candidate variants could show robust associations in manageable study samples6. This approach is less feasible if the genetic risk from a given candidate gene is due to many infrequent alleles. Previous studies of several genes demonstrated that most variants are relatively infrequent2,3 (<0.05). These surveys genotyped small samples (n<75) and thus had limited ability to identify rare alleles. Here we evaluate the prevalence and distribution of such rare alleles by genotyping an ethnically diverse reference sample that is more than six times larger than those used in previous studies8 (n=450). We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter9,10. Both genes have unique roles in neuronal transmission, and variants in either gene might be associated with neurobehavioral phenotypes11,12,13.

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Acknowledgements

We thank E. Lander and D. Altshuler for SLC6A4 primer sequences, and M. Slatkin, I. Herskowitz and L.A. McInnes for helpful discussions. This work was supported by grants MH01375, MH49499 and GM61390 from the National Institutes of Health. C.E.G. was supported by a grant from the Klingenstein Third Generation Foundation.

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Author notes

  1. Charles E. Glatt & Nelson B. Freimer
    Present address: UCLA Center for Neurobehavioral Genetics, Gonda Center, Los Angeles, California, USA

Authors and Affiliations

  1. Neurogenetics Laboratory, Program in Human Genetics, University of California San Francisco, San Francisco, California, USA
    Charles E. Glatt, Sharon Delgado, Susan K. Service & Nelson B. Freimer
  2. Department of Psychiatry, Program in Human Genetics, University of California San Francisco, San Francisco, California, USA
    Charles E. Glatt & Nelson B. Freimer
  3. Genomics Core Facility, Program in Human Genetics, University of California San Francisco, San Francisco, California, USA
    Joseph A. DeYoung
  4. Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA
    Kathleen M. Giacomini
  5. Department of Neurology and Physiology, University of California San Francisco, San Francisco, California, USA
    Robert H. Edwards
  6. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
    Neil Risch

Authors

  1. Charles E. Glatt
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  2. Joseph A. DeYoung
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  3. Sharon Delgado
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  4. Susan K. Service
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  5. Kathleen M. Giacomini
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  6. Robert H. Edwards
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  7. Neil Risch
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  8. Nelson B. Freimer
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Corresponding author

Correspondence toNelson B. Freimer.

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Glatt, C., DeYoung, J., Delgado, S. et al. Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes.Nat Genet 27, 435–438 (2001). https://doi.org/10.1038/86948

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