Abstract:We previously mapped loci for the genome-wide association studies (GWAS) and genome-wide gene-by-alcohol dependence interaction (GW-GxAD) analyses of risky sexual behaviors (RSB). This study extends those findings by analyzing the ancestry- and sex-specific AD-stratified effects on RSB. We examined the concordance of findings for the AD-stratified GWAS and the GW-GxAD analysis of RSB, with concordance defined as genome-wide significance in one analysis and at least nominal significance in the second analysis. … Show more
“…Inhibition of FAM134A causes impaired proteostasis in the endoplasmic reticulum due to the accumulation of misfolded proteins, which has been implicated in vascular dementia [ 45 ]. FAM162A is associated by GWAS to a gene-by-alcohol dependence interaction study of risky sexual behaviors and so it could be related to behavioral control [ 46 ]. Coincidentally, ADHD is associated with increased sexual risk taking [ 47 ].…”
Background
A variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited.
Methods
Using well defined cohorts of discordant, monozygotic twins from the Michigan State University Twin Registry, and case-controlled ADHD cases in adolescents, the present studies utilized advanced single molecule RNA sequencing to identify expressed changes in whole blood RNA in ADHD. Multiple analytical strategies were employed to narrow differentially expressed RNA targets to a small set of potential biomarkers of ADHD.
Results
RNA markers common to both the discordant twin study and case-controlled subjects further narrowed the putative targets, some of which had been previously associated with ADHD at the DNA level. The potential role of several differentially expressed genes, including ABCB5, RGS2, GAK, GIT1 and 3 members of the galactose metabolism pathway (GALE, GALT, GALK1) are substantiated by prior associations to ADHD and by established mechanistic connections to molecular pathways relevant to ADHD and behavioral control.
Conclusions
The convergence of DNA, RNA, and metabolic data suggests these may be promising targets for diagnostics and therapeutics in ADHD.
“…Inhibition of FAM134A causes impaired proteostasis in the endoplasmic reticulum due to the accumulation of misfolded proteins, which has been implicated in vascular dementia [ 45 ]. FAM162A is associated by GWAS to a gene-by-alcohol dependence interaction study of risky sexual behaviors and so it could be related to behavioral control [ 46 ]. Coincidentally, ADHD is associated with increased sexual risk taking [ 47 ].…”
Background
A variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited.
Methods
Using well defined cohorts of discordant, monozygotic twins from the Michigan State University Twin Registry, and case-controlled ADHD cases in adolescents, the present studies utilized advanced single molecule RNA sequencing to identify expressed changes in whole blood RNA in ADHD. Multiple analytical strategies were employed to narrow differentially expressed RNA targets to a small set of potential biomarkers of ADHD.
Results
RNA markers common to both the discordant twin study and case-controlled subjects further narrowed the putative targets, some of which had been previously associated with ADHD at the DNA level. The potential role of several differentially expressed genes, including ABCB5, RGS2, GAK, GIT1 and 3 members of the galactose metabolism pathway (GALE, GALT, GALK1) are substantiated by prior associations to ADHD and by established mechanistic connections to molecular pathways relevant to ADHD and behavioral control.
Conclusions
The convergence of DNA, RNA, and metabolic data suggests these may be promising targets for diagnostics and therapeutics in ADHD.
“…Here we unexpectedly observed a profound decrease of Avpi1 transcript levels in the nPE1 +/+ hypothalamus after chronic alcohol drinking (Figure D), suggesting for the first time the potential interaction between the AVP‐induced protein 1 and excessive alcohol drinking or withdrawal. Of interest, in a recent human genetic study, rs7913179 variant in the Avpi1 gene is found to associate with alcohol dependency in a genome‐wide gene‐by‐alcohol dependence interaction analysis in European men . Although the AVP/V1b receptor system plays important roles in alcohol drinking, it seems unknown, however, whether and how the hypothalamic AVP‐induced protein 1 is involved in alcohol drinking behaviors, and further study is needed.…”
Section: Discussionmentioning
confidence: 99%
“…Of interest, in a recent human genetic study, rs7913179 variant in the Avpi1 gene is found to associate with alcohol dependency in a genome-wide gene-by-alcohol dependence interaction analysis in European men. 53 Although the AVP/V1b receptor system plays important roles in alcohol drinking, 11,15 it seems unknown, however, whether and how the hypothalamic AVP-induced protein 1 is involved in alcohol drinking behaviors, and further study is needed.…”
Section: Genetically Determined Differences In Stress Genes Transcrmentioning
Persistent alterations of proopiomelanocortin (Pomc) and mu‐opioid receptor (Oprm1) activity and stress responses after alcohol are critically involved in vulnerability to alcohol dependency. Gene transcriptional regulation altered by alcohol may play important roles. Mice with genome‐wide deletion of neuronal Pomc enhancer1 (nPE1−/−), had hypothalamic‐specific partial reductions of beta‐endorphin and displayed lower alcohol consumption, compared to wildtype littermates (nPE1+/+). We used RNA‐Seq to measure steady‐state nuclear mRNA transcripts of opioid and stress genes in hypothalamus of nPE1+/+ and nPE1−/− mice after 1‐day acute withdrawal from chronic excessive alcohol drinking or after water. nPE1−/− had lower basal Pomc and Pdyn (prodynorphin) levels compared to nPE1+/+, coupled with increased basal Oprm1 and Oprk1 (kappa‐opioid receptor) levels, and low alcohol drinking increased Pomc and Pdyn to the basal levels of nPE1+/+ in the water group, without significant effects on Oprm1 and Oprk1. In nPE1+/+, excessive alcohol intake increased Pomc and Oprm1, with no effect on Pdyn or Oprk1. For stress genes, nPE1−/− had lowered basal Oxt (oxytocin) and Avp (arginine vasopressin) that were restored by low alcohol intake to basal levels of nPE1+/+. In nPE1+/+, excessive alcohol intake decreased Oxt and Avpi1 (AVP‐induced protein1). Functionally examining the effect of pharmacological blockade of mu‐opioid receptor, we found that naltrexone reduced excessive alcohol intake in nPE1+/+, but not nPE1−/−. Our results provide evidence relevant to the transcriptional profiling of the critical genes in mouse hypothalamus: enhanced opioid and reduced stress gene transcripts after acute withdrawal from excessive alcohol may contribute to altered reward and stress responses.
“…Inhibition of FAM134A causes impaired proteostasis in the endoplasmic reticulum due to the accumulation of misfolded proteins, which has been implicated in vascular dementia [45]. FAM162A is associated by GWAS to a gene-by-alcohol dependence interaction study of risky sexual behaviors and so it could be related to behavioral control [46]. Coincidentally, ADHD is associated with increased sexual risk taking [47].…”
Section: Analysis Of Differentially Expressed Genesmentioning
Background: A variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited. Methods: Using well defined cohorts of discordant, monozygotic twins from the Michigan State University Twin Registry, and case-controlled ADHD cases in adolescents, the present studies utilized advanced single molecule RNA sequencing to identify expressed changes in whole blood RNA in ADHD. Multiple analytical strategies were employed to narrow differentially expressed RNA targets to a small set of potential biomarkers of ADHD. Results: RNA markers common to both the discordant twin study and case-controlled subjects further narrowed the putative targets, some of which had been previously associated with ADHD at the DNA level. The potential role of several differentially expressed genes, including ABCB5, RGS2, GAK, GIT1 and 3 members of the galactose metabolism pathway (GALE, GALT, GALK1) are substantiated by prior associations to ADHD and by established mechanistic connections to molecular pathways relevant to ADHD and behavioral control.Conclusions: The convergence of DNA, RNA, and metabolic data suggests these may be promising targets for diagnostics and therapeutics in ADHD.
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