ABSTRACT The somatostatin receptor 5 (SSTR5) gene is a candidate gene for bipolar affective disorder (BPAD) as well as for other neuropsychiatric disorders. The gene is positioned on

chromosome 16p13.3, a region that has been implicated by a few linkage studies to potentially harbor a disease susceptibility gene for BPAD. Recent evidence shows that the dopamine D2

receptor (DRD2) and SSTR5 interact physically to form heterodimers with enhanced functional activity. Brain D2 dopamine receptors are one of the major targets of neuroleptic treatments in

psychiatric disorders. In this study we systematically screened the promoter and coding region of the SSTR5 gene for genetic variation that could contribute to the development of

suggested between silent SNP G573A and BPAD (_P_ = 0.008). For the British population we found association to BPAD with missense mutation Leu48Met (_P_ = 0.003) and missense mutation

Pro335Leu (_P_ = 0.004). The statistical significance of the association was, however, greatly reduced after correcting for multiple testing. When combining genotypes from Leu48Met and

Pro335Leu into haplotypes, association to BPAD was found in the British population (_P_ = 0.0007). This haplotype association was not replicated in the Danish population. Our results may

indicate that the SSTR5 gene is involved in the etiology of BPAD or may exist in linkage disequilibrium with a susceptibility gene close to SSTR5. However, given the marginal statistical

significance and the potential for false-positive results in association studies with candidate genes, further studies are needed to clarify this hypothesis. Access through your institution

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OTHERS POSITIONAL CLONING AND COMPREHENSIVE MUTATION ANALYSIS OF A JAPANESE FAMILY WITH LITHIUM-RESPONSIVE BIPOLAR DISORDER IDENTIFIES A NOVEL _DOCK5_ MUTATION Article 12 September 2020 THE

CONSERVED _ASTN2_/_BRINP1_ LOCUS AT 9Q33.1–33.2 IS ASSOCIATED WITH MAJOR PSYCHIATRIC DISORDERS IN A LARGE PEDIGREE FROM SOUTHERN SPAIN Article Open access 15 July 2021 GENOME-WIDE

ASSOCIATION STUDY OF PATIENTS WITH A SEVERE MAJOR DEPRESSIVE EPISODE TREATED WITH ELECTROCONVULSIVE THERAPY Article 22 January 2021 NOTES * D16S85 was found on compound Z69706 and D16S521

was found on compound Z69719, both on contig NT_000655, at URL: http://www.ncbi.nlm.nih.gov/genome/guide/HsChr16.shtml. REFERENCES * Ewald H, Mors O, Flint T, Koed K, Eiberg H, Kruse TA . A

possible locus for manic depressive illness on chromosome 16p13 _Psychiatr Genet_ 1995; 5: 71–81 Article  CAS  PubMed  Google Scholar  * Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal

A _et al_. A comprehensive genetic map of the human genome based on 5264 microsatellites _Nature_ 1996; 380: 152–154 Article  CAS  PubMed  Google Scholar  * Edenberg HJ, Foroud T, Conneally

PM, Sorbel JJ, Carr K, Crose C _et al_. Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 3, 5, 15, 16, 17, and 22 _Am J Med Genet_ 1997; 74: 238–246

Article  CAS  PubMed  Google Scholar  * McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S _et al_. A complete genome screen for genes predisposing to severe bipolar disorder in

two Costa Rican pedigrees _Proc Natl Acad Sci USA_ 1996; 93: 13060–13065 Article  CAS  PubMed  PubMed Central  Google Scholar  * Levitas AS, Reid CS . Rubinstein–Taybi syndrome and

psychiatric disorders _J Intellect Disabil Res_ 1998; 42: 284–292 Article  PubMed  Google Scholar  * Adams LJ, Salmon JA, Kwok JB, Vivero C, Donald JA, Mitchell PB _et al_. Exclusion of

linkage between bipolar affective disorder and chromosome 16 in 12 Australian pedigrees _Am J Med Genet_ 1997; 74: 304–310 Article  CAS  PubMed  Google Scholar  * Blackwood DH, He L, Morris

SW, McLean A, Whitton C, Thomson M _et al_. A locus for bipolar affective disorder on chromosome 4p _Nat Genet_ 1996; 12: 427–430 Article  CAS  PubMed  Google Scholar  * Coon H, Jensen S,

Hoff M, Holik J, Plaetke R, Reimherr F _et al_. A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance _Am J Hum Genet_ 1993; 52: 1234–1249

CAS  PubMed  PubMed Central  Google Scholar  * Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G _et al_. A high-density genome scan detects evidence for a

bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2 _Proc Natl Acad Sci USA_ 1999; 96: 5604–5609 Article  CAS  PubMed  PubMed Central  Google Scholar

  * Friddle C, Koskela R, Ranade K, Hebert J, Cargill M, Clark CD _et al_. Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype _Am J Hum Genet_

2000; 66: 205–215 Article  CAS  PubMed  Google Scholar  * Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagne B _et al_. Genome-wide search for linkage of bipolar affective

disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23–q24 _Am J Med Genet_ 1999; 88: 567–587 Article  CAS

  PubMed  Google Scholar  * Murphy VE, Mynett-Johnson LA, Claffey E, Bergin P, McAuliffe M, Kealey C _et al_. Search for bipolar disorder susceptibility loci: the application of a modified

genome scan concentrating on gene-rich regions _Am J Med Genet_ 2000; 96: 728–732 Article  CAS  PubMed  Google Scholar  * Ewald H, Kruse TA . Bipolar affective disorder, chromosome 16p13.3,

and recessive disease genes [letter] _Am J Med Genet_ 1997; 74: 549–550 Article  CAS  PubMed  Google Scholar  * Takeda J, Fernald AA, Yamagata K, Le Beau MM, Bell GI . Localization of human

somatostatin receptor 5 gene (SSTR5) to chromosome band 16p13.3 by fluorescence in situ hybridization _Genomics_ 1995; 26: 638–639 Article  CAS  PubMed  Google Scholar  * Deloukas P, Schuler

GD, Gyapay G, Beasley EM, Soderlund C, Rodriguez-Tome P _et al_. A physical map of 30 000 human genes _Science_ 1998; 282: 744–746 Article  CAS  PubMed  Google Scholar  * Brazeau P, Vale W,

Burgus R, Ling N, Butcher M, Rivier J _et al_. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone _Science_ 1973; 179: 77–79 Article  CAS 

PubMed  Google Scholar  * Patel YC, Greenwood MT, Panetta R, Demchyshyn L, Niznik H, Srikant CB . The somatostatin receptor family _Life Sci_ 1995; 57: 1249–1265 Article  CAS  PubMed  Google

Scholar  * Rubinow DR, Davis CL, Post RM . Somatostatin in neuropsychiatric disorders _Prog Neuropsychopharmacol Biol Psychiatry_ 1988; 12: 137–155 Article  Google Scholar  * Bissette G,

Myers B . Somatostatin in Alzheimer's disease and depression _Life Sci_ 1992; 51: 1389–1410 Article  CAS  PubMed  Google Scholar  * Patel YC . Somatostatin and its receptor family

_Front Neuroendocrinol_ 1999; 20: 157–198 Article  CAS  PubMed  Google Scholar  * Panetta R, Greenwood MT, Warszynska A, Demchyshyn LL, Day R, Niznik HB _et al_. Molecular cloning,

functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28 _Mol Pharmacol_ 1994;

45: 417–427 CAS  PubMed  Google Scholar  * Yamada Y, Kagimoto S, Kubota A, Yasuda K, Masuda K, Someya Y _et al_. Cloning, functional expression and pharmacological characterization of a

fourth (hSSTR4) and a fifth (hSSTR5) human somatostatin receptor subtype _Biochem Biophys Res Commun_ 1993; 195: 844–852 Article  CAS  PubMed  Google Scholar  * Rocheville M, Lange DC, Kumar

U, Patel SC, Patel RC, Patel YC . Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity _Science_ 2000; 288: 154–157 Article  CAS  PubMed

  Google Scholar  * American Psychiatric Association. _Diagnostic and Statistical Manual of Mental Disorder, 4th edn_ APA: Washington DC 1994 * Sanger F, Nicklen S, Coulson AR . DNA

sequencing with chain-terminating inhibitors _Proc Natl Acad Sci USA_ 1977; 74: 5463–5467 Article  CAS  PubMed  PubMed Central  Google Scholar  * Lathrop GM, Lalouel JM, Julier C, Ott J .

Strategies for multilocus linkage analysis in humans _Proc Natl Acad Sci USA_ 1984; 81: 3443–3446 Article  CAS  PubMed  PubMed Central  Google Scholar  * Terwilliger JD, Ott J . _Handbook of

Human Genetic Linkage_ The John Hopkins University Press: Baltimore 1994 Google Scholar  * Sham PC, Curtis D . Monte Carlo tests for associations between disease and alleles at highly

polymorphic loci _Ann Hum Genet_ 1995; 59: 97–105 Article  CAS  PubMed  Google Scholar  * Lewontin RC . The interaction of selection and linkage. I. General consideration; heterotic models

_Genetics_ 1964; 49: 49–67 CAS  PubMed  PubMed Central  Google Scholar  * Greenwood MT, Panetta R, Robertson LA, Liu JL, Patel YC . Sequence analysis of the 5′-flanking promoter region of

the human somatostatin receptor 5 _Biochem Biophys Res Commun_ 1994; 205: 1883–1890 Article  CAS  PubMed  Google Scholar  * Quandt K, Frech K, Karas H, Wingender E, Werner T . MatInd and

MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data _Nucleic Acids Res_ 1995; 23: 4878–4884 Article  CAS  PubMed  PubMed Central  Google

Scholar  * Sasi R, Puebla L, Khare S, Patel YC . Polymorphism in the 5′ flanking region of the human somatostatin receptor subtype 5 _Gene_ 1998; 214: 45–49 Article  CAS  PubMed  Google

Scholar  * Thompson EA, Deeb S, Walker D, Motulsky AG . The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes _Am J Hum Genet_

1988; 42: 113–124 CAS  PubMed  PubMed Central  Google Scholar  * Przeworski M, Hudson RR, Di Rienzo A . Adjusting the focus on human variation _Trends Genet_ 2000; 16: 296–302 Article  CAS 

PubMed  Google Scholar  * Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S _et al_. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a

population-based study of presenile Alzheimer disease _Hum Mol Genet_ 1998; 7: 43–51 Article  CAS  PubMed  Google Scholar  * Patel YC, Greenwood M, Panetta R, Hukovic N, Grigorakis S,

Robertson LA _et al_. Molecular biology of somatostatin receptor subtypes _Metabolism_ 1996; 45: 31–38 Article  CAS  PubMed  Google Scholar  * Hukovic N, Panetta R, Kumar U, Rocheville M,

Patel YC . The cytoplasmic tail of the human somatostatin receptor type 5 is crucial for interaction with adenylyl cyclase and in mediating desensitization and internalization _J Biol Chem_

1998; 273: 21416–21422 Article  CAS  PubMed  Google Scholar  * Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA _et al_. Results of a genome-wide genetic screen for panic

disorder _Am J Med Genet_ 1998; 81: 139–147 Article  CAS  PubMed  Google Scholar  * International Molecular Genetic Study of Autism Consortium. A full genome screen for autism with evidence

for linkage to a region on chromosome 7q _Hum Mol Genet_ 1998; 7: 571–578 * Ewald H, Mors O, Eiberg H . Linkage analysis between manic-depressive illness and 35 classical markers _Am J Med

Genet_ 1994; 54: 144–148 Article  CAS  PubMed  Google Scholar  * Risch N, Merikangas K . The future of genetic studies of complex human diseases _Science_ 1996; 273: 1516–1517 Article  CAS 

PubMed  Google Scholar  * Long AD, Langley CH . The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits _Genome Res_ 1999; 9:

720–731 CAS  PubMed  PubMed Central  Google Scholar  * Martin ER, Lai EH, Gilbert JR, Rogala AR, Afshari AJ, Riley J _et al_. SNPing away at complex diseases: analysis of single-nucleotide

polymorphisms around APOE in Alzheimer disease _Am J Hum Genet_ 2000; 67: 383–394 Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS The SSTR5 clone

used in this study was kindly provided by Dr Graeme I Bell, Howard Hughes Medical Institute. We thank Drs Robert Plomin (SGDP Centre) and Simon Lovestone (Old Age Psychiatry) for access to

the British control samples. This work was supported by the Danish Medical Research Council (9303757, 9602007, 9902685, 9902769), Fonden til Laegevidenskabens Fremme, Fonden til Psykiatriens

Fremme, The Psychiatric Research Foundation, The Eli and Egon Larsen Foundation, The Geert-Jørgensen Foundation, The Axel Thomsen Foundation, The Trier-Hansen Foundation, and The Jacob

Madsen Foundation. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Clinical Biochemistry and Genetics, Odense University Hospital, Denmark M Nyegaard & T A Kruse * Institute

of Human Genetics, Aarhus University, Denmark A D Børglum * Mood Disorders Research Unit, Psychiatric Hospital in Aarhus, Denmark T G Bruun * Department of Psychological Medicine, Institute

of Psychiatry, London, UK D A Collier & C Russ * Institute for Basic Psychiatric Research, Psychiatric Hospital in Aarhus, Denmark O Mors & H Ewald Authors * M Nyegaard View author

publications You can also search for this author inPubMed Google Scholar * A D Børglum View author publications You can also search for this author inPubMed Google Scholar * T G Bruun View

author publications You can also search for this author inPubMed Google Scholar * D A Collier View author publications You can also search for this author inPubMed Google Scholar * C Russ

View author publications You can also search for this author inPubMed Google Scholar * O Mors View author publications You can also search for this author inPubMed Google Scholar * H Ewald

View author publications You can also search for this author inPubMed Google Scholar * T A Kruse View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to M Nyegaard. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Nyegaard, M., Børglum, A., Bruun, T. _et al._ Novel

polymorphisms in the somatostatin receptor 5 (SSTR5) gene associated with bipolar affective disorder. _Mol Psychiatry_ 7, 745–754 (2002). https://doi.org/10.1038/sj.mp.4001049 Download

citation * Received: 09 July 2001 * Revised: 09 August 2001 * Accepted: 15 November 2001 * Published: 23 August 2002 * Issue Date: 01 August 2002 * DOI: https://doi.org/10.1038/sj.mp.4001049

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to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * SSTR5 * chromosome 16p13.3 * candidate gene * bipolar disorder * DNA mutational analysis * genetic

variation * SNP * linkage disequilibrium * haplotype analysis * association study