1. ¹Institute of Human Genetics, University of Bonn, Bonn, Germany
2. ²Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
3. ³Department of Genomics, Life and Brain Center, Bonn, Germany

Correspondence: Dr J Freudenberg, Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, Bonn D-53111, Germany. Tel: +49 228 287 2581; Fax: +49 228 287 2380; E-mail: jan.freudenberg@uni-bonn.de

⁴These authors contributed equally to this work.

⁵Current address: Laboratories of Neurogenetics, UCSF, 1550 4th Street, San Francisco, CA 94143-2922, USA

Received 18 October 2005; Revised 18 April 2006; Accepted 25 April 2006; Published online 31 May 2006.

Abstract

In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100 000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human–rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes.