1. ¹Biognosis US, Inc. (Dissolved). From the Price Foundation Collaborative Group
2. ²University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
3. ³Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
4. ⁴National Institute of Alcohol Abuse and Alcoholism, Rockville, MD, USA
5. ⁵Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, USA
6. ⁶Department of Psychology, Michigan State University, East Lansing, MI, USA
7. ⁷Klinik Roseneck, Hospital for Behavioral Medicine, Munich, Germany
8. ⁸New York Presbyterian Hospital-Westchester, Weill Medical College of Cornell University, White Plains, New York, USA
9. ⁹Department of Psychiatry, The Toronto Hospital, Toronto, Canada
10. ¹⁰Neuropsychiatric Institute and Hospital, School of Medicine, University of California at Los Angeles, Los Angeles, USA
11. ¹¹Institute of Psychiatry, Maudsley and Bethlehem Royal Hospital, London, UK
12. ¹²Eating Disorders Module, Western Psychiatric Institute & Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Correspondence: WH Kaye, MD, Department of Psychiatry, 3811 O'Hara St, 600 Iroquois Building, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. E-mail: kayewh@msx.upmc.edu

¹³Current address: Core Genotyping Facility, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20877, USA.

¹⁴Current address: Division of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK.

¹⁵Current address: Core Genotyping Facility, Advanced Technology Center, National Cancer Institute/SAIC, Gaithersburg, MD 20877, USA.

¹⁶These two authors contributed equally.

^*This manuscript does not represent the opinion of the NIH, DHHS, or the Federal Government.

Received 5 December 2001; Revised 31 October 2002; Accepted 8 November 2002.

Abstract

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3–34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21–5.75) for HTR1D and 1.61 (95% CI=1.11–2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.