Browsing by Author "Jager, Philip L. De"

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    Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis
    (Springer Nature, 2018-08) Kowalec, Kaarina; Wright, Galen E.B.; Drögemöller, Britt I.; Aminkeng, Folefac; Bhavsar, Amit P.; Kingwell, Elaine; Yoshida, Eric M.; Traboulsee, Anthony; Marrie, Ruth Ann; Kremenchutzky, Marcelo; Campbell, Trudy L.; Duquette, Pierre; Chalasani, Naga; Wadelius, Mia; Hallberg, Pär; Xia, Zongqi; Jager, Philip L. De; Denny, Joshua C.; Davis, Mary F.; Ross, Colin J.D.; Tremlett, Helen; Carleton, Bruce C.; Medicine, School of Medicine
    Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10-8, odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10-5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use.
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    Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria
    (Wiley, 2019-06-04) Lai, Dongbing; Wetherill, Leah; Bertelsen, Sarah; Carey, Caitlin E.; Kamarajan, Chella; Kapoor, Manav; Meyers, Jacquelyn L.; Anokhin, Andrey P.; Bennett, David A.; Bucholz, Kathleen K.; Chang, Katharine K.; Jager, Philip L. De; Dick, Danielle M.; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John I.; Raj, Towfique; Schuckit, Marc; Scott, Denise M.; Taylor, Robert E.; Tischfield, Jay; Hariri, Ahmad R.; Edenberg, Howard J.; Agrawal, Arpana; Bogdan, Ryan; Porjesz, Bernice; Goate, Alison M.; Foroud, Tatiana; Medical and Molecular Genetics, School of Medicine
    Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (e.g., ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWASs of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7,418 (1,121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3,175 (585 families) African American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (p=4.16E-11) and Desire to cut drinking (p=1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, p=6.72E-09); rs1912461 (chromosome 15, Time spent drinking, p=1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, p=8.42E-11); rs7597960 (chromosome 2, Time spent drinking, p=1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (p<0.01; 0.61-1.82% of variance). Identified novel variants (i.e., rs1912461, rs61826952) were associated with differential central evoked theta power (loss minus gain; p=0.0037) and reward-related ventral striatum reactivity (p=0.008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.