Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.Peer reviewe

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Impact of HIV/SIV infection and antiretroviral treatment on adipose tissue alterations : role of fibrosis and aging

Le tissu adipeux (TA) est affecté lors de l’infection par le virus de l’immunodéficience humaine (VIH) puisqu’il est ciblé simultanément par le virus et les antirétroviraux (ARV). Les perturbations des fonctions métaboliques et sécrétoires du TA ont des répercussions sur l’ensemble de l’organisme participant aux atteintes cardiométaboliques. Premièrement, j’ai démontré l’impact du virus lui-même sur la dysfonction du TA au travers de modèles in vivo (TA issus de macaques ou de patients infectés), et in vitro de cellules souches adipocytaires humaines (ASC). J’ai mis en évidence que le TA issu de macaques ou de patients infectés présente une fibrose accrue, de petits adipocytes et une augmentation de marqueurs de vieillissement. En accord, les protéines du VIH Tat et Nef induisent une accumulation de collagènes, une sénescence, un stress oxydant, des dysfonctions mitochondriales et altèrent l’adipogenèse des ASC. Deuxièmement, je me suis intéressée à l’impact des inhibiteurs d’intégrase (INI) sur le TA. En effet, une prise de poids plus importante, liée à une augmentation du TA, a récemment été observée chez les patients infectés par le VIH recevant une combinaison d’ARV comprenant un INI. In vivo, dans le TA de macaques non infectés mais traités par des INI, j’ai mis en évidence une fibrose péri-adipocytaire accrue, associée à une hypertrophie adipocytaire. J’ai démontré in vitro que malgré leur effet proadipogénique, le traitement par les INI abouti à la formation d’adipocytes dysfonctionnels résistants à l’insuline. Mon travail a permis d’évaluer les effets respectifs du VIH et des INI dans les atteintes du TA et de mieux comprendre les mécanismes en cause.Adipose tissue (AT) is a tissue affected during infection with the human immunodeficiency virus (HIV) as it is simultaneously targeted by the virus and antiretroviral therapy (ART). Alteration of AT metabolic and secretory functions have whole body consequences which contribute to cardiometabolic diseases. First, I demonstrated the impact of HIV itself on AT dysfunction using two in vivo models (AT from infected macaques or patients), and an in vitro model of human adipocyte stem cells (ASCs). I showed that AT from macaques or from infected individuals displayed increased fibrosis, small adipocytes and increased markers of aging. In agreement, the HIV proteins Tat and Nef induced collagen accumulation, senescence, oxidative stress, mitochondrial dysfunctions, and altered adipogenesis of ASCs. Secondly, I evaluated the impact of Integrase Strand Transfer Inhibitors (INSTIs) on AT. Indeed, a greater weight gain; linked to an increase in AT, has recently been demonstrated in patients infected with HIV and receiving an ART regimen containing an INSTI. In vivo, AT of uninfected but INSTI treated macaques, presented increased peri-adipocyte fibrosis, associated with adipocyte hypertrophy. I have demonstrated in vitro that despite their proadipogenic effect, INSTI-treatment led to the formation of dysfunctional insulin-resistant adipocytes. My PhD allowed to assess the effects of HIV infection and INTIIs on AT alterations and to better understand the mechanisms involved

Impacts de l'infection par le VIH/VIS et des antirétroviraux sur les atteintes du tissu adipeux : rôle de la fibrose et du vieillissement

Adipose tissue (AT) is a tissue affected during infection with the human immunodeficiency virus (HIV) as it is simultaneously targeted by the virus and antiretroviral therapy (ART). Alteration of AT metabolic and secretory functions have whole body consequences which contribute to cardiometabolic diseases. First, I demonstrated the impact of HIV itself on AT dysfunction using two in vivo models (AT from infected macaques or patients), and an in vitro model of human adipocyte stem cells (ASCs). I showed that AT from macaques or from infected individuals displayed increased fibrosis, small adipocytes and increased markers of aging. In agreement, the HIV proteins Tat and Nef induced collagen accumulation, senescence, oxidative stress, mitochondrial dysfunctions, and altered adipogenesis of ASCs. Secondly, I evaluated the impact of Integrase Strand Transfer Inhibitors (INSTIs) on AT. Indeed, a greater weight gain; linked to an increase in AT, has recently been demonstrated in patients infected with HIV and receiving an ART regimen containing an INSTI. In vivo, AT of uninfected but INSTI treated macaques, presented increased peri-adipocyte fibrosis, associated with adipocyte hypertrophy. I have demonstrated in vitro that despite their proadipogenic effect, INSTI-treatment led to the formation of dysfunctional insulin-resistant adipocytes. My PhD allowed to assess the effects of HIV infection and INTIIs on AT alterations and to better understand the mechanisms involved.Le tissu adipeux (TA) est affecté lors de l’infection par le virus de l’immunodéficience humaine (VIH) puisqu’il est ciblé simultanément par le virus et les antirétroviraux (ARV). Les perturbations des fonctions métaboliques et sécrétoires du TA ont des répercussions sur l’ensemble de l’organisme participant aux atteintes cardiométaboliques. Premièrement, j’ai démontré l’impact du virus lui-même sur la dysfonction du TA au travers de modèles in vivo (TA issus de macaques ou de patients infectés), et in vitro de cellules souches adipocytaires humaines (ASC). J’ai mis en évidence que le TA issu de macaques ou de patients infectés présente une fibrose accrue, de petits adipocytes et une augmentation de marqueurs de vieillissement. En accord, les protéines du VIH Tat et Nef induisent une accumulation de collagènes, une sénescence, un stress oxydant, des dysfonctions mitochondriales et altèrent l’adipogenèse des ASC. Deuxièmement, je me suis intéressée à l’impact des inhibiteurs d’intégrase (INI) sur le TA. En effet, une prise de poids plus importante, liée à une augmentation du TA, a récemment été observée chez les patients infectés par le VIH recevant une combinaison d’ARV comprenant un INI. In vivo, dans le TA de macaques non infectés mais traités par des INI, j’ai mis en évidence une fibrose péri-adipocytaire accrue, associée à une hypertrophie adipocytaire. J’ai démontré in vitro que malgré leur effet proadipogénique, le traitement par les INI abouti à la formation d’adipocytes dysfonctionnels résistants à l’insuline. Mon travail a permis d’évaluer les effets respectifs du VIH et des INI dans les atteintes du TA et de mieux comprendre les mécanismes en cause