ORCID Profile
0000-0002-1724-5405
Current Organisations
Yale University
,
Texas A & M University
,
National Institutes of Health
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Publisher: Elsevier BV
Date: 03-1999
DOI: 10.1086/302282
Publisher: Elsevier BV
Date: 06-1998
DOI: 10.1086/301867
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-04-2021
DOI: 10.1002/HEP.31535
Abstract: Only a minority of heavy drinkers progress to alcohol‐associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy‐drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome‐wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta‐analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome‐wide significant risk association of rs738409 in patatin‐like phospholipase domain containing 3 ( PNPLA3 ) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10 −17 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10 −10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas‐associated factor family member 2 ( FAF2 ) (OR = 0.61 [del(T) allele], P = 2.56 × 10 −8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta‐analysis (without conditioning) confirmed genome‐wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13 . Two other previously known loci ( SERPINA1 and SUGP1/TM6SF2 ) were also genome‐wide significant in the meta‐analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
Publisher: Elsevier BV
Date: 12-2020
Publisher: BMJ
Date: 28-03-2006
Publisher: American Medical Association (AMA)
Date: 09-2003
Publisher: Wiley
Date: 16-02-2020
DOI: 10.1111/ADB.12880
Publisher: Springer Science and Business Media LLC
Date: 27-10-2009
Publisher: Springer Science and Business Media LLC
Date: 23-07-2021
DOI: 10.1038/S41386-021-01097-0
Abstract: Naltrexone can aid in reducing alcohol consumption, while ac rosate supports abstinence however, not all patients with alcohol use disorder (AUD) benefit from these treatments. Here we present the first genome-wide association study of AUD treatment outcomes based on data from the COMBINE and PREDICT studies of ac rosate and naltrexone, and the Mayo Clinic CITA study of ac rosate. Primary analyses focused on treatment outcomes regardless of pharmacological intervention and were followed by drug-stratified analyses to identify treatment-specific pharmacogenomic predictors of ac rosate and naltrexone response. Treatment outcomes were defined as: (1) time until relapse to any drinking (TR) and (2) time until relapse to heavy drinking (THR ≥ 5 drinks for men, ≥4 drinks for women in a day), during the first 3 months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies ( N = 1083 European ancestry participants). Single nucleotide polymorphisms (SNPs) in the BRE gene were associated with THR (min p = 1.6E−8) in the entire s le, while two intergenic SNPs were associated with medication-specific outcomes (naltrexone THR: rs12749274, p = 3.9E−8 ac rosate TR: rs77583603, p = 3.1E−9). The top association signal for TR ( p = 7.7E−8) and second strongest signal in the THR ( p = 6.1E−8) analysis of naltrexone-treated patients maps to PTPRD , a gene previously implicated in addiction phenotypes in human and animal studies. Leave-one-out polygenic risk score analyses showed significant associations with TR ( p = 3.7E−4) and THR ( p = 2.6E−4). This study provides the first evidence of a polygenic effect on AUD treatment response, and identifies genetic variants associated with potentially medication-specific effects on AUD treatment response.
Publisher: Springer Science and Business Media LLC
Date: 02-09-1998
Abstract: A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global s le of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four in idual markers include three TaqI restriction site polymorphisms (RSPs) -- TaqI "A", "B", and "D" sites -- and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most in idual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population s le. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P<0.001) in all 28 populations. Except for three African s les, the pairwise disequilibrium between the outermost RSP markers, TaqI "B" and "A", was highly significant with D' values greater than 0.8 in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI "B" site in all populations, with D' values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an "Out of Africa" model for recent human evolution.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2018
No related grants have been discovered for David Goldman.