👤 W Berrettini

Compared to DBA/2J (D2), C57BL/6J (B6) inbred mice exhibit strong morphine preference when tested using a two-bottle choice drinking paradigm. A morphine preference quantitative trait locus (QTL), Mop2, was originally mapped to proximal chromosome (Chr) 10 using a B6xD2 F2 intercross population, confirmed with reciprocal congenic strains and fine mapped with recombinant congenic strains. These efforts identified a ∼ 10-Million base pair (Mbp) interval, underlying Mop2, containing 35 genes. To further reduce the interval, mice from the D2.B6-Mop2-P1 congenic strain were backcrossed to parental D2 mice and two new recombinant strains of interest were generated: D2.B6-Mop2-P1.pD.dB and D2.B6-Mop2-P1.pD.dD. Results obtained from testing these strains in the two-bottle choice drinking paradigm suggest that the gene(s) responsible for the Mop2 QTL is one or more of 22 remaining within the newly defined interval (∼ 7.6 Mbp) which includes Oprm1 and several other genes related to opioid pharmacology. Real-time qRT-PCR analysis of Oprm1 and opioid-related genes Rgs17, Ppp1r14c, Vip, and Iyd revealed both between-strain and within-strain expression differences in comparisons of saline- and morphine-treated B6 and D2 mice. Analysis of Rgs17 protein levels also revealed both between-strain and within-strain differences in comparisons of saline- and morphine-treated B6 and D2 mice. Results suggest that the Mop2 QTL represents the combined influence of multiple genetic variants on morphine preference in these two strains. Relative contributions of each variant remain to be determined. Show less

Anorexia nervosa (AN) is a mental illness with high mortality that most commonly afflicts adolescent female individuals. Clinical symptoms include chronic food refusal, weight loss and body image distortions. We carried out a genome-wide association study on 1033 AN cases and 3733 pediatric control subjects, all of whom were of European ancestry and were genotyped on the Illumina HumanHap610 platform (Illumina, San Diego, CA, USA). We confirmed that common single-nucleotide polymorphisms (SNPs) within OPRD1 (rs533123, P=0.0015) confer risk for AN, and obtained suggestive evidence that common SNPs near HTR1D (rs7532266, P=0.04) confer risk for restricting-type AN specifically. However, no SNPs reached genome-wide significance in our data, whereas top association signals were detected near ZNF804B, CSRP2BP, NTNG1, AKAP6 and CDH9. In parallel, we performed genome-wide analysis on copy number variations (CNVs) using the signal intensity data from the SNP arrays. We did not find evidence that AN cases have more CNVs than control subjects, nor do they have over-representation of rare or large CNVs. However, we identified several regions with rare CNVs that were only observed in AN cases, including a recurrent 13q12 deletion (1.5 Mb) disrupting SCAS in two cases, and CNVs disrupting the CNTN6/CNTN4 region in several AN cases. In conclusion, our study suggests that both common SNPs and rare CNVs may confer genetic risk to AN. These results point to intriguing genes that await further validation in independent cohorts for confirmatory roles in AN. Show less