Addictions Biology: Haplotype-Based Analysis for 130 Candidate Genes on a Single Array

Laboratory of Neurogenetics, NIAAA, 5625 Fishers Lane, Room 3S32 MSC9412, Rockville, MD 20852-1728, USA.
Alcohol and Alcoholism (Impact Factor: 2.89). 06/2008; 43(5):505-15. DOI: 10.1093/alcalc/agn032
Source: PubMed


To develop a panel of markers able to extract full haplotype information for candidate genes in alcoholism, other addictions and disorders of mood and anxiety.
A total of 130 genes were haplotype tagged and genotyped in 7 case/control populations and 51 reference populations using Illumina GoldenGate SNP genotyping technology, determining haplotype coverage. We also constructed and determined the efficacy of a panel of 186 ancestry informative markers.
An average of 1465 loci were genotyped at an average completion rate of 91.3%, with an average call rate of 98.3% and replication rate of 99.7%. Completion and call rates were lowered by the performance of two datasets, highlighting the importance of the DNA quality in high throughput assays. A comparison of haplotypes captured by the Addictions Array tagging SNPs and commercially available whole-genome arrays from Illumina and Affymetrix shows comparable performance of the tag SNPs to the best whole-genome array in all populations for which data are available.
Arrays of haplotype-tagged candidate genes, such as this addictions-focused array, represent a cost-effective approach to generate high-quality SNP genotyping data useful for the haplotype-based analysis of panels of genes such as these 130 genes of interest to alcohol and addictions researchers. The inclusion of the 186 ancestry informative markers allows for the detection and correction for admixture and further enhances the utility of the array.

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Available from: Colin A Hodgkinson
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    • "A minimum minor allele frequency (MAF) based on the Hap Map CEU of 10% was chosen. Genes and SNPs were selected based on identified opioid biological pathways and adult opioid-dependence literature (Gelernter et al., 2014; Goldman et al., 2006; Hodgkinson et al., 2008; Kreek et al., 2006; Levran et al., 2012, 2008; Li et al., 2011; Lotsch et al., 2004). The SNPs selected were from genes of the opioid-receptor family and/or related to the endogenous stress pathway (Table 1). "
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    ABSTRACT: There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability. Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated. SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level. These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · Drug and alcohol dependence
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    • "DNA was extracted from immortalized cell lines, blood, or saliva. The subjects were genotyped using the Illumina HumanOmni1-Quad platform with 1 140 419 predesigned probes (Illumina, San Diego, California) (Hodgkinson et al, 2008). Genotyping was conducted at the Yale Center for Genome Analysis and the Center for Inherited Disease Research (CIDR). "
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    ABSTRACT: Single nucleotide polymorphisms that have been associated with opioid dependence (OD) altogether account for only a small proportion of the known heritability. Most of the genetic risk factors are unknown. Some of the "missing heritability" might be explained by copy number variations (CNVs) in the human genome. We used Illumina HumanOmni1 arrays to genotype 5,152 African-American and European-American OD cases and screened controls and implemented combined CNV calling methods. After quality control measures were applied, a genomewide association study (GWAS) of CNVs with OD was performed. For common CNVs, two deletions and one duplication were significantly associated with OD genomewide (e.g., P=2 × 10(-8) and OR (95% CI)=0.64 (0.54-0.74) for a chromosome 18q12.3 deletion). Several rare or unique CNVs showed suggestive or marginal significance with large effect sizes. This study is the first GWAS of OD using CNVs. Some identified CNVs harbor genes newly identified here to be of biological importance in addiction, while others affect genes previously known to contribute to substance dependence risk. Our findings augment our specific knowledge of the importance of genomic variation in addictive disorders, and provide an addiction CNV pool for further research. These findings require replication.Neuropsychopharmacology accepted article preview online, 27 October 2014. doi:10.1038/npp.2014.290.
    Full-text · Article · Oct 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "The samples were also genotyped for 150 ancestry informative markers (AIMs) (Hodgkinson et al, 2008), from which individual ethnic factor scores were computed (Supplementary Materials). The 4 ethnic factor scores explaining the highest variance (Table 2) "
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    ABSTRACT: Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and externalizing behaviors. We investigated the impact of GABRA2 on the developmental trajectory of nucleus accumbens (NAcc) activation during anticipation of monetary reward from childhood to young adulthood. Functional MRI during a monetary incentive delay task was collected in 175 participants, with the majority (n=151) undergoing repeated scanning at one- to two-year intervals. One group entered the study at age 8-13 (n=76) and another entered at age 18-23 (n=99). Most participants were children of alcoholics (79%) and thus at heightened risk for AUD. A total of 473 sessions were completed, covering ages 8-27. NAcc activation was heightened during adolescence compared to childhood and young adulthood. GABRA2 genotype (SNP rs279858) was associated with individual differences in NAcc activation specifically during adolescence, with the minor allele (G) associated with greater activation. Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n=104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development.Neuropsychopharmacology accepted article preview online, 30 June 2014; doi:10.1038/npp.2014.161.
    Full-text · Article · Jun 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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