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PubMed2001

Molecular phylogeny and divergence time estimates for major rodent groups: evidence from multiple genes.

The order Rodentia contains half of all extant mammal species, and from an evolutionary standpoint, there are persistent controversies surrounding the monophyly of the order, divergence dates for major lineages, and relationships among families. Exons of growth hormone receptor (GHR) and breast cancer susceptibility (BRCA1) genes were sequenced for a wide diversity of rodents and other mammals and combined with sequences of the mitochondrial 12S rRNA gene and previously published sequences of von Willebrand factor (vWF). Rodents exhibit rates of amino acid replacement twice those observed for nonrodents, and this rapid rate of evolution influences estimates of divergence dates. Based on GHR sequences, monophyly is supported, with the estimated divergence between hystricognaths and most sciurognaths dating to about 75 MYA. Most estimated dates of divergence are consistent with the fossil record, including a date of 23 MYA for Mus-Rattus divergence. These dates are considerably later than those derived from some other molecular studies. Among combined and separate analyses of the various gene sequences, moderate to strong support was found for several clades. GHR appears to have greater resolving power than do 12S or vWF. Despite its complete unresponsiveness to growth hormone, Cavia (and other hystricognaths) exhibits a conservative rate of change in the intracellular domain of GHR.

Animals↗
PubMed1999

Genetic markers to predict polygenic disease: a new problem for social genetics.

Many genetic markers that relate to common multifactorial disease in adults have been identified during the past 15 years. Their use as adjuncts for the diagnosis, prognosis, prediction of disease or targeting therapy for these disorders has begun, good examples being the Factor V Leiden mutation for venous-thromboembolism, lipoprotein lipase mutations for hypertriglyceridaemia and the apolipoprotein E4 variant for Alzheimer's dementia. However, extensive gene-gene and gene-environment interactions make their use more complex than markers for the simpler monogenic disorders (such as cystic fibrosis, or Duchenne's muscular dystrophy). Possible misapplication of the genetic markers for multifactorial disease in the fields of risk prediction, direct sales to the public, life assurance, employment rights, and legislation for regulation of their use are discussed.

Adult↗
PubMed2025

Genetic Susceptibility to the Environment Moderates the Impact of Childhood Experiences on Psychotic, Depressive, and Anxiety Dimensions.

BACKGROUND AND HYPOTHESIS: Gene-by-environment (GxE) studies in psychosis have exclusively focused on negative exposures. However, evidence supports the resilience-enhancing effect of positive factors on psychosis outcome. The Differential Susceptibility (DS) model proposes that common genetic variants may confer not only disproportionate responsiveness to negative environments, but also greater sensitivity to positive, resilience-enhancing conditions. This study is the first to apply the DS model to the expression of subclinical psychosis, employing polygenic risk scores of environmental sensitivity (PRS-ES). PRS-ES were hypothesized to moderate, in a DS manner, associations between childhood adversity and psychosis, affective, and anxiety dimensions in young adults. An exploratory goal examined whether PRS for psychotic-like experiences (PRS-PLE) also showed DS patterns. STUDY DESIGN: PRS, schizotypy, PLE, depression, anxiety, and childhood adversity ratings were obtained for 197 nonclinical young adults. LEGIT software for testing competitive-confirmatory GxE models was employed. STUDY RESULTS: Results largely supported DS: Individuals high on PRS-ES showed increased subclinical psychosis, depression, and anxiety if they had experienced elevated childhood adversity, and lower symptoms if exposed to low levels of adversity as compared with those with low PRS-ES. Similarly, PRS-PLE moderated the effect of adversity on PLE, positive schizotypy, and depression following the DS model, but only PRS-ES moderation on PLE survived statistical correction. CONCLUSIONS: Our results suggest that genetic DS to the environment is relevant to psychosis, depression, and anxiety. Current debates on reconceptualization of genetic "risk" and resilience may benefit from this insight that support optimistic views on preventative efforts for early detection and intervention.

Humans↗
PubMed2025

Genetic Differences in Reactivity to the Environment Impact Psychotic-Like and Affective Reactivity in Daily Life.

BACKGROUND AND HYPOTHESIS: Consistent with diathesis-stress models, psychosis research has focused on genetic moderation of adverse environmental exposures. In contrast, the Differential Susceptibility (DS) model suggests that the same genetic variants that increase risk-inducing effects of adverse experiences also enhance beneficial effects from positive experiences. This study examined whether individuals with high genetic susceptibility to the environment showed differential psychotic-like and affective reactivity in response to positive and negative events in daily life. STUDY DESIGN: Experience sampling methodology assessed context (positive and stressful) and momentary levels of paranoia, psychotic-like experiences (PLE), and positive (PA) and negative affect (NA) in 217 non-clinical adults oversampled for schizotypy. Linear mixed models examined whether Polygenic Risk Scores of Environmental Sensitivity (PRS-ES) moderated the impact of current context on subsequent experiences. STUDY RESULTS: PRS-ES moderated positive, but not stressful, context on subsequent levels of momentary paranoia, NA, and PA, but not PLE. Genetic and environmental (G × E) interactions indicated diathesis-stress at lower thresholds of PRS-ES, but a DS model at the highest threshold of the PRS-ES. Participants with elevated PRS-ES showed increased paranoia and NA and decreased PA in subsequent assessments when reporting low levels of positive situations, but also decreased paranoia and NA and increased PA when rating contexts as positive. CONCLUSIONS: Findings support the influence of genetic sensitivity to the environment on psychotic-like and affective reactivity in daily life, particularly in response to positive contexts. This highlights the transdiagnostic protective role of positive experiences and informs ecological momentary interventions.

Humans↗
PubMed2025

Genetic prediction of early adolescent chronotype: effects of sex and pubertal status.

STUDY OBJECTIVES: Adolescence is characterized by later sleep onset and wake times, indicating a shift to an evening chronotype. Genome-wide association studies (GWAS) in adults show chronotype is polygenic and causally linked to depression, schizophrenia, and cognitive function. Yet, the impact of genetics on adolescent chronotype remains largely unexplored, and biological factors influencing the predictive relationship between genetics and chronotype have not been well-defined. This study aims to assess the utility of polygenic scores (PGS) derived from adult GWAS in predicting adolescent chronotype, mental health, and cognition while considering sex- and puberty-dependent effects. METHODS: Generalized linear models were used to assess the relationship between PGS for chronotype and self-reported chronotype, mental health, and cognition in 2411 youths of European ancestry aged 10-13 years. Interaction terms assessed whether the genotype-phenotype relationships varied by sex or pubertal development. Statistical significance was determined using a likelihood ratio test. RESULTS: Significant sex- and puberty-dependent effects were observed. Higher PGS for morningness concordantly predicted earlier self-reported chronotype, but in female youth only. Follow-up analyses showed that sex-specific effects were mediated by the interaction between PGS and pubertal status. Greater genetic predisposition for morningness was negatively associated with somnolence and cognition in males and negatively associated with psychotic-like experiences in females. CONCLUSIONS: The influence of genetic predisposition for early versus late chronotype on adolescent sleep-wake behavior emerges as puberty progresses. These findings suggest puberty is a critical transition when genetic variants associated with chronotype in adults become relevant to pediatric cohorts.

Humans↗
PubMed2002

Long-term divergent selection on fatness in mice indicates a regulation system independent of leptin production and reception.

Divergent selection in mice on fatness over 60 generations produced a fat (F) and a lean (L) line, having about 22% and 4% body fat, respectively. To elucidate the importance of the leptin regulatory feedback loop in the genetic changes produced by this selection, Lep(ob) and Lepr(db) mutations causing leptin production and leptin receptor deficiency, respectively, were introgressed individually into both lines by repeated backcrossing. The fat amount increased significantly in homozygotes for Lep(ob) or Lepr(db) in both lines, for example, in F and L males from 8.5 to 18.8 and 17.2 g (P<0.001) and from 1.25 to 18.0 and 12.7 g (P<0.001), respectively. Line differences were, however, mostly maintained after introgression. Concentrations of circulating leptin were relatively independent of the original lines but heavily dependent on the introgressed genotype. Introgression of leptin production and receptor deficiencies had separate effects from long-term selection, indicating that the genes responsible for the line divergence must act independently of the leptin regulatory system. Energy budget analysis indicated that the major line differences were in the level of energy expended on physical activity, and these differences were preserved following introgression, suggesting that multiple pathways regulate fatness, which may be independently responsive to intervention.

Adipose Tissue↗
PubMed2001

WHP/ISBRA study on state and trait markers in alcoholism.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Boris Tabakoff. The presentations were (1) Overview of the WHO/ISBRA study on state and trait markers in alcoholism, by Boris Tabakoff; (2) Biochemical markers of acute and chronic drinking: Results of the WHO/ISBRA study, by Anders Helander; (3) The impact of country of recruitment and body mass index on biological marker dose-response curves in the WHO/ISBRA Study, by Kate M. Conigrave; (4) Relationship of body water to carbohydrate-deficient transferrin measures, by Larry Martinez; and (5) Platelet adenylyl cyclase activity as a trait marker of alcohol dependence, by Paula L. Hoffman.

Adenylyl Cyclases↗
PubMed2003

Role of genetics in prevention of coronary atherosclerosis.

Atherosclerosis is currently regarded as a complex disorder, triggered by gene-gene and gene-environment interactions. Despite the difficulties of multifactorial disease genetic analysis, significant progress has been achieved in the search for atherosclerosis susceptibility genes. Here, we review these advances with regard to genome scan results and candidate gene analysis.

Coronary Artery Disease↗
PubMed2001

Non-association of the thiazide-sensitive Na,Cl-cotransporter gene with polygenic hypertension in both rats and humans.

OBJECTIVE: Genes underlying renal regulation of sodium and water balances are a priori valid candidates for polygenic hypertension susceptibility genes. Having recently identified the association of alpha1 Na,K-ATPase (ATP1A1) and Na,K,2Cl-cotransporter (NKCC2) as interacting hypertension susceptibility loci in both a rat model and human hypertensives, we investigated whether the thiazide-sensitive Na,Cl-cotransporter (TSC) gene contributes to hypertension susceptibility in a rat F2 intercross and in a northern Sardinian human cohort for polygenic hypertension. SUBJECTS AND METHODS: The rat TSC (rTSC) gene was analyzed directly for cosegregation with salt-sensitive hypertension in an F2 (Dahl S x Dahl R) rat population (n = 102) characterized for blood pressure by radiotelemetry. The human TSC (hTSC) gene was analyzed for association with hypertension in a human hypertensive cohort from northern Sardinia that consisted of 220 unrelated normotensives and 254 unrelated hypertensives. The TSC gene was subjected to single locus and digenic (in combination with ATP1A1 and NKCC2 genes) analyses in both rat and human cohorts. RESULTS: In both rat model and human cohorts, the rTSC and hTSC genes did not show linkage or association with high blood pressure, respectively. Furthermore, interaction with either ATP1A1 or NKCC2 was not detected in both the rat F2 intercross and human hypertension cohorts. CONCLUSIONS: These data exclude a primary role of the TSC gene in hypertension pathogenesis in the hypertension cohorts studied.

Alleles↗
PubMed2003

How genetics changes daily practice.

Develop a firmer understanding of the role genetics plays in health and disease, and incorporate genetic questions into patient assessment.

Confidentiality↗
PubMed1994

Genetics review: relation to ocular disease.

This study is a review of modes of transmission of genetic traits, how they relate to ocular diseases, and abnormalities frequently seen by primary eye care practitioners. Traits showing autosomal dominant (AD), autosomal recessive (AR), X-linked (XR) recessive, chromosomal aberrations, and multifactorial (M) inheritance are listed. General guidelines for genetic counseling are given.

Chromosome Aberrations↗
PubMed2003

Cardiovascular disease genetics: a long and winding road.

PURPOSE OF REVIEW: This review has two major goals. The first goal is to raise some of the methodological problems associated with studying the genetics of complex disorders, specifically cardiovascular diseases. The second is to update the reader with the most recent findings in the area of genotype-phenotype associations as well as the interaction between genetic factors and cardiovascular disease risk markers, with emphasis on those related to lipid metabolism. RECENT FINDINGS: In terms of new information, three topics are presented: (1) new findings related to classical candidate genes, such as apolipoprotein E, cholesteryl ester transfer protein and hepatic lipase; (2) recent reports related to new loci that have joined the growing list of cardiovascular disease candidate genes (i.e. ATP-binding cassette transporters A1 and C6, peroxisome proliferator activated receptor alpha, interleukin-6); and (3) studies showing that multiple genes appear to be at the intersection of several age-related disorders such as cardiovascular disease, neurological disorders and osteoporosis (i.e. apolipoprotein E, vitamin D receptor, matrix Gla protein, peroxisome proliferator activated receptor gamma, angiotensin-converting enzyme, estrogen receptor, androgen receptor, methylenetetrahydrofolate reductase). SUMMARY: The dramatic increase in our ability to carry out genotyping is creating a tremendous wealth of information in terms of associations between genetic markers and biochemical or clinical phenotypes. Increased attention, however, should be placed on study design and replication of findings. This should also be facilitated by the inclusion of multiple markers per loci in order to provide a more precise definition of the alleles associated with the phenotypes of interest. Moreover, given the fact that most of the phenotypes are equally affected by genetic and environmental factors, studies should emphasize the analyses of their interaction.

Cardiovascular Diseases↗
PubMed2006

Predictive testing for complex diseases using multiple genes: fact or fiction?

PURPOSE: There is ongoing debate about whether testing low-risk genes at multiple loci will be useful in clinical care and public health. We investigated the usefulness of multiple genetic testing using simulated data. METHODS: Usefulness was evaluated by the area under the receiver-operating characteristic curve (AUC), which indicates the accuracy of genetic profiling in discriminating between future patients and nonpatients. The AUC was investigated in relation to the number of genes assumed to be involved, the risk allele frequency, the odds ratio of the risk genotypes, and to the proportion of variance explained by genetic factors as an approximation of the heritability of the disease. RESULTS: We demonstrated that a high (AUC > 0.80) to excellent discriminative accuracy (AUC > 0.95) can be obtained by simultaneously testing multiple susceptibility genes. A higher discriminative accuracy is obtained when genetic factors play a larger role in the disease, as indicated by the proportion of explained variance. The maximum discriminative accuracy of future genetic profiling can be estimated at present from the heritability and prevalence of disease. CONCLUSIONS: Genetic profiling may have the potential to identify individuals at higher risk of disease depending on the prevalence and heritability of the disease.

Area Under Curve↗
PubMed2006

Genetic variants predisposing to cardiovascular disease.

PURPOSE OF REVIEW: The goal of this review is to provide an update on the most recent and relevant findings in the area of genotype-phenotype associations as well as the relationships between genetic factors and cardiovascular disease risk markers and events. In addition, emphasis will be placed on the methodological problems associated with studying the genetics of complex disorders, specifically cardiovascular diseases. RECENT FINDINGS: Genes associated with cardiovascular disease predisposition have been examined, including traditional cardiovascular disease candidate genes, such as ACE, AGT, eNOS, PON and MTHFR, new loci that have recently been added to the growing list of cardiovascular disease candidate genes (i.e. MEF2A, ALOX5, LTA, APOM, PDE4D), and genes that have been shown to be at the intersection of several age-related disorders through interaction with one another or with environmental factors (i.e. APOA5, APOE, PPARgamma, LPL and LIPC). SUMMARY: During the last year, tremendous effort has been made in elucidating new genes associated with cardiovascular disease predisposition. For the most part, however, major breakthroughs have not been made, primarily due to the poor replication of results among studies, as a consequence of poor experimental design. Nevertheless, we have increased our understanding of the complexity of cardiovascular disease and the relevance of gene-environment interactions as the ultimate drivers of the individual predisposition to the disease. It is essential, therefore, that present and future genetic studies in this area take into consideration the inclusion of high-quality environmental data in the analytical process to test the clinical usefulness of a genetic marker as a risk predictor.

Cardiovascular Diseases↗
PubMed2025

Predicting Weight Loss After Vertical Sleeve Gastrectomy Using a Whole-genome Sequencing-derived Polygenic Risk Score in the All of Us Cohort.

OBJECTIVE: To create a genome-wide polygenic risk score (PRS) to improve prediction of a 12-month percentage weight loss (WL) after vertical sleeve gastrectomy (VSG). BACKGROUND: Variability in post-VSG WL is not well explained by clinical factors. The All of Us program provides access to a 414,830 short-read whole-genome sequencing resource, enabling unbiased discovery of genetic predictors after VSG. METHODS: VSG counts, demographic, anthropomorphic and vital sign information were obtained from the linked electronic health record. The discovery cohort (DC) included participants from version 7 carried into version 8 while the validation cohort (VC) included those newly added to v8. We defined good responders and nonresponders as having WL&#xb1;1SD from the mean. Following quality filtering, we applied a 2-stage penalized-regression, followed by elastic-net logistic regression, to identify 1583 stable variants and derive &#x3b2;-weights. We then tested this PRS on the DC into a prediction model. RESULTS: We identified 395 participants in the DC and 336 participants in the VC, respectively. Of these, VSG, 44 were classified as good responders (&#x2265;37% WL) and 55 as nonresponders (&#x2264;19% WL). In the VC, 55 were classified as good responders and 48 as nonresponders. Adding the PRS to models to clinical predictors increased the area under the curve following logistic regression by 0.03; P <4.3 &#xd7; 10 -14 , random forest by 0.03; P <9.1 &#xd7; 10 -7 , decision tree by 0.05; P = 1.2 &#xd7; 10 -3 , and gradient boosting by 0.08; P <8.3 &#xd7; 10 -10 . CONCLUSIONS: Use of short-read whole-genome sequencing from All of Us (AoU) can be effectively used to generate PRS to enhance predictive WL accuracy. This work has implications for outcomes of both bariatric surgery and other surgical procedures.

Humans↗