HIGH THROUGHPUT SNP IDENTIFICATION. LNG has discovered over 100 single nucleotide polymorphisms (SNPs) in more than 50 neuro-genetic candidate genes for addictive behaviors, including alcoholism. Approximately 20% of the SNPs discovered by LNG result in non-synonymous amino acid changes that may alter function of the encoded protein or alterations in expression of the gene. The implications of detected sequence variation have been profound: for example a rare serotonin transporter variant we found was shown to be functional and discovered to lead to severe pathology: Asperger's syndrome, treatment resistant OCD, and anorexia nervosa, in two families in which it is segregating, and a third common allele of the serotonin transporter promoter polymorphism (HTTLPR) which leads to altered function and enabled detection of linkage of the gain-of-function LA allele to OCD in two populations. For example, the common HTR2C Ser23Cys and HTR2A Asn452His alleles have been shown to be functional and linked to the clozapine responsiveness of schizophrenics. Genes for SNP screening were selected on the basis of postulated roles in alcohol, treatment response, identification in whole genome or candidate linkage or association study, and the availability of genomic sequence data. Because a goal of the project is to determine the role of SNPs in complex genetic disorders, we focused our screening in efforts on protein coding portions of the candidate gene and possible regulatory regions within and flanking the protein coding regions. We used a DNA panel composed of 477 genomic DNAs enriched for clinical and ethnic diversity. HIGH THROUGHPUT GENOTYPING. Central issues in high throughput genotyping procedures are accuracy, flexibility, and cost. Because of its assay design flexibility, low error rate, and potential for performing 96 to 384 assays simultaneously, we have used some 1,000 individual 5' exonuclease assays. We also use SNPlex, a DNA ligation method, in which pools of 48 SNPs are simultaneously genotyped, with detection on an ABI capillary sequencer and DNA preparation using robotics. Regarding array-based genotyping, we have created a 1536 SNP ?Addictions Array.? This array enables haplotype-based and candidate locus coverage of some 122 genes, including genes important in the domains of alcohol metabolism, stress/anxiety, monoamine function, and signaling. The array also includes 200 genomic control loci for detecting, and correcting, ethnic stratification in case control studies. Use of the ?Addictions Array? by Extramural investigators will be facilitated.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Intramural Research (Z01)
Project #
1Z01AA000301-07
Application #
7146665
Study Section
(LNG)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Dubey, N; Hoffman, J F; Schuebel, K et al. (2017) The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Mol Psychiatry 22:1172-1184
Yeo, Seungeun; Hodgkinson, Colin A; Zhou, Zhifeng et al. (2016) The abundance of cis-acting loci leading to differential allele expression in F1 mice and their relationship to loci harboring genes affecting complex traits. BMC Genomics 17:620
Lindell, Stephen G; Yuan, Qiaoping; Zhou, Zhifeng et al. (2012) The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: potential roles in genetic selection and gene × environment interactions. Dev Psychopathol 24:1391-400
Lipsky, Robert H; Hu, Xian-Zhang; Goldman, David (2009) Additional functional variation at the SLC6A4 gene. Am J Med Genet B Neuropsychiatr Genet 150B:153
Zhou, Zhifeng; Zhu, Guanshan; Hariri, Ahmad R et al. (2008) Genetic variation in human NPY expression affects stress response and emotion. Nature 452:997-1001
Anton, Raymond F; Oroszi, Gabor; O'Malley, Stephanie et al. (2008) An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry 65:135-44
Nugent, Allison C; Neumeister, Alexander; Goldman, David et al. (2008) Serotonin transporter genotype and depressive phenotype determination by discriminant analysis of glucose metabolism under acute tryptophan depletion. Neuroimage 43:764-74
Krystal, John H; Carter, Cameron S; Geschwind, Daniel et al. (2008) It is time to take a stand for medical research and against terrorism targeting medical scientists. Biol Psychiatry 63:725-7
Blair, K S; Finger, E; Marsh, A A et al. (2008) The role of 5-HTTLPR in choosing the lesser of two evils, the better of two goods: examining the impact of 5-HTTLPR genotype and tryptophan depletion in object choice. Psychopharmacology (Berl) 196:29-38
Reba-Harrelson, Lauren; Von Holle, Ann; Thornton, Laura M et al. (2008) Features associated with diet pill use in individuals with eating disorders. Eat Behav 9:73-81

Showing the most recent 10 out of 79 publications