Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research

<p>Abstract</p> <p>Background</p> <p>GABA transporter-1 (GAT-1; genetic locus <it>SLC6A1</it>) is emerging as a novel target for treatment of neuropsychiatric disorders. To understand how population differences might influence strategies for pharmacogenetic studies, we identified patterns of genetic variation and linkage disequilibrium (LD) in <it>SLC6A1 </it>in five populations representing three continental groups.</p> <p>Results</p> <p>We resequenced 12.4 kb of <it>SLC6A1</it>, including the promoters, exons and flanking intronic regions in African-American, Thai, Hmong, Finnish, and European-American subjects (total n = 40). LD in <it>SLC6A1 </it>was examined by genotyping 16 SNPs in larger samples. Sixty-three variants were identified through resequencing. Common population-specific variants were found in African-Americans, including a novel 21-bp promoter region variable number tandem repeat (VNTR), but no such variants were found in any of the other populations studied. Low levels of LD and the absence of major LD blocks were characteristic of all five populations. African-Americans had the highest genetic diversity. European-Americans and Finns did not differ in genetic diversity or LD patterns. Although the Hmong had the highest level of LD, our results suggest that a strategy based on the use of tag SNPs would not translate to a major improvement in genotyping efficiency.</p> <p>Conclusion</p> <p>Owing to the low level of LD and presence of recombination hotspots, <it>SLC6A1 </it>may be an example of a problematic gene for association and haplotype tagging-based genetic studies. The 21-bp promoter region VNTR polymorphism is a putatively functional candidate allele for studies focusing on variation in GAT-1 function in the African-American population.</p

Substance use disorders in adolescence: comorbidity, temporality of onset and socio-demographic background:a study of adolescent psychiatric inpatients in Northern Finland

Abstract Over 90% of addicts start substance use during adolescence. There are few studies focusing on the comorbidity and temporality of substance dependence among adolescents. The aim of this study was to investigate the comorbidity and temporality of substance use disorders, to identify the factors leading to intravenous drug dependence and to evaluate the psychotropic medication history among adolescents. The study population comprised a sample of 508 (300 girls) 12- to 17-year-old hospitalized inpatients during a defined 5-year period. Substance use and other psychiatric disorders were identified according to DSM-IV criteria and adolescents’ socio-demographic and substance use background was examined. The main findings of the present study include the following: The most common comorbidities of alcohol and drug dependence are behavioral, depressive and phobic disorders; Phobic and behavioral disorders develop generally prior to the onset of alcohol and drug dependence; Drug dependent boys are more likely to have depression than girls (IV); In adolescence, phobic disorders may influence the development of secondary substance dependence within a few years from the onset of phobia (I); Behavioral disorders are associated with earlier initiation of daily smoking, and earlier age of onset of daily smoking is associated with an increased risk for alcohol and drug dependence (III); Adolescents with intravenous drug dependence start experiment with drugs at young age, often before the age of 10 years, and present more commonly with parental absence and troubled school background (II); Prescribed benzodiazepine medication is associated with an increased risk of sedative dependence (V). These findings imply that psychiatric comorbidity plays a pivotal role in the development of substance use disorders in adolescence. Those adolescents who experiment with substances at a young age are at greatest risk of substance dependence and intravenous drug use before the age of 18. Family dynamics seem to play an important role in this development. The psychotropic medication history of substance-using adolescents often differs greatly from current evidence-based guidelines and is dominated by those medications that are frequently abused.Tiivistelmä Yli 90 % päihdeongelmaisista aloittaa päihteidenkäytön nuoruusiällä. Silti päihdehäiriöiden ja niihin liittyvän psykiatrisen sairastavuuden – komorbiditeetin ja tämän ajallisen ilmenemisen – temporaliteetin - tutkimus nuorisoväestössä on suppeaa. Väitöskirjatutkimuksen tarkoituksena oli kartoittaa nuoruusiän päihdehäiriöiden komorbiditeetin ja temporaliteetin ominaispiirteitä, selventää taustalla olevia sosiodemografisia tekijöitä, sekä arvioida päihdehäiriöisten nuorten reseptilääkehistoriaa päihdehäiriöiden synnyn ymmärtämiseksi. Tutkimusaineisto koostui 508 (300 tyttöä) 12-17-vuotiaasta akuuttia psykiatrista sairaalahoitoa tarvitsevasta potilaista. Nuorten psykiatrinen- ja päihdesairastavuus selvitettiin DSM-IV diagnoosijärjestelmän mukaisesti, sekä sosiodemografinen tausta kartoitettiin kattavasti. Alkoholi- ja huumeriippuvaisilla nuorilla yleisimpiä komorbideja häiriöitä olivat käytös-, masennus- ja pelkohäiriöt. Pelko- ja käytöshäiriöt ilmenivät yleensä ajallisesti ennen alkoholi- ja huumeriippuvuutta. Huumeriippuvaisilla pojilla oli tyttöjä useammin masennusta (IV). Pelkohäiriöt vaikuttivat sekundaarisen päihderiippuvuuden kehittymiseen mahdollisesti jo muutamien vuosien kuluessa pelkohäiriöiden ilmenemisestä (I). Käytöshäiriöt liittyivät aikaisempaan päivittäisen tupakoinnin aloittamiseen joka liittyy edelleen sekä alkoholi- että huumeriippuvuuteen (III). Suonensisäisen huumeidenkäytön aloittaminen nuorella iällä liittyi selkeästi vanhemmattomaan kotiin, sekä jo ala-asteella alkaneisiin koulunkäyntiongelmiin. Vaikeimmin päihderiippuvaisten nuorten päihteidenkäyttökokeilut alkoivat merkittävän nuorena, jo onnen 10 ikävuotta ala-asteella (II). Bentsodiatsepiinien reseptilääkkekäyttö sairaalahoitoa aiemmin liittyi merkittävästi sedatiiviriippuvuuteen (V). Löydösten perusteella psykiatrisella sairastavuudella on merkittävää rooli päihdehäiriön kehittymisessä jo nuoruusiällä. Nuoret, joiden päihdekokeilut alkavat varhain, ovat suurimmassa riskissä riippuvuuteen ja ajautumiseen suonensisäiseen käyttöön. Päihderiippuvaisilla nuorilla on lisäksi taipumus sekä reseptilääkkeiden väärinkäyttöön, että kykyä näiden hankkimiseen - myös lääkärin määräämänä

Illustration of the 21 bp insertion/deletion polymorphism (long and short alleles) and the insertion/deletion GG allele in the gene

<p><b>Copyright information:</b></p><p>Taken from "Sequence variation and linkage disequilibrium in the GABA transporter-1 gene () in five populations: implications for pharmacogenetic research"</p><p>http://www.biomedcentral.com/1471-2156/8/71</p><p>BMC Genetics 2007;8():71-71.</p><p>Published online 17 Oct 2007</p><p>PMCID:PMC2175509.</p><p></p> Picture (A) shows position of -24794 A/G SNP, 21 bp insertion and GG deletion. Picture (B) shows the sequence for the short and long alleles and the -24794 A/G SNP. The A allele of the -24794 always coincided with the long allele in our populations. Sequence for the GG insertion/deletion polymorphism is presented in picture (C)

Illustration of the LD structure and recombination hotspots in the 5 populations

<p><b>Copyright information:</b></p><p>Taken from "Sequence variation and linkage disequilibrium in the GABA transporter-1 gene () in five populations: implications for pharmacogenetic research"</p><p>http://www.biomedcentral.com/1471-2156/8/71</p><p>BMC Genetics 2007;8():71-71.</p><p>Published online 17 Oct 2007</p><p>PMCID:PMC2175509.</p><p></p> Upper graphs illustrate elevations from the background recombination rates across the gene. Y axis represent recombination rate and X axis represents physical distance between the markers [19, 20]. In Figure A, recombination rates for HapMap CEPH Western Europeans (CEU) and European-Americans of the present study are presented. In Figure B, recombination rates for HapMap Yoruban (YRI) and African-Americans of the present study are presented. In Figure C, recombination rates for HapMap combined Han Chinese and Japanese populations (HCB+JPT) and the Thais of the present study are presented. In Figures D and E, recombination rates for the Finns and Hmongs of the present study are presented. In the middle, the exon-intron structure of and location of the markers is presented. LD (D') between the SNPs in is illustrated in the lower triangular graphs

Lorand Andahazy or Yura Lazovsky as a Polovtsien Warrior (centre front), and artists of the company, in Prince Igor, The Original Ballet Russe, Australian tour, His Majesty's Theatre, Melbourne, April 1940 [picture] /

From: Prince Igor : Polovtsien dances from the opera Prince Igor / music by Aleksandr Borodin.; Inscription: "3Q/32".; Part of the collection: Hugh P. Hall collection of photographs, 1938-1940.; Choreography by Michel Fokine ; scenery and costumes by Nicholas Roerich.; Also available in an electronic version via the internet at: http://nla.gov.au/nla.pic-vn4180295. One of a collection of photographs taken by Hugh P. Hall of 28 ballet productions performed by the Covent Garden Russian Ballet (toured Australia 1938-1939) and the Original Ballet Russe (toured Australia 1939-1940). These are the second and third of the three Ballets Russes companies which toured Australasia between 1936 and 1940. The photographs were taken from the auditorium during a live performance in His Majesty's Theatre, Melbourne and mounted on cardboard for display purposes. For conservation and storage, the photographs have been demounted. The original arrangement of the photographs has been recorded, and details are available from the Pictures Branch of the National Library