Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Frequency of self-reinforcement, perceived control, and depression in Asian and Caucasian community-dwelling elders

Thesis (Ph. D.)--University of Hawaii at Manoa, 1996.Includes bibliographical references (leaves 134-145).Microfiche.ix, 145 leaves, bound 29 cmThis study was concerned with the extent to which behavioral competencies of self-reinforcement and perceived control covary or predict depression concurrently and at a later point in time. It was also concerned with whether there are significant differences between Asian American and Caucasian American elders in terms of depression, frequency of self-reinforcement, and perceived control. The study found no significant differences between Asian American and Caucasian American elders in depression mean scores. The results showed that a lower frequency of self-reinforcement was significantly associated with a higher level of depression concurrently and five months later for both Asian and Caucasian participants. Asian elders reported significantly lower self-reinforcement scores than Caucasian elders. In contrast, low perceived control was significantly associated with higher level of depression concurrently and five months later for Caucasian elders only. Asian elders reported significantly lower perceived control scores than Caucasian elders. The role of behavioral competencies in accounting for concurrent and future depression scores and the ethnic subsample differences in self-reinforcement and perceived control scores are discussed

Negative thinking versus positive thinking in a Singaporean student sample : relationships with psychological well-being and psychological maladjustment

This study examines the relationships of positive thinking versus negative thinking with psychological well-being and psychological maladjustment. Three hundred and ninety-eight undergraduate students from Singapore participated in this study. First, positive thinking were positively correlated with indicators psychological well-being – life satisfaction and happiness, and negatively correlated with indicators of psychopathology – stress, anxiety, depression, and anger. In contrast, negative thinking were positively correlated with indicators of psychopathology – stress, anxiety, depression, and anger, and negatively correlated with indicators of psychological well-being – life satisfaction and happiness. Second, hierarchical multiple regression results showed that females were more likely than males to be stressed and anxious at the first step of entry. However, there were no significant differences between the sexes in terms of depression, anger, life satisfaction, and happiness. Age did not significantly predict any of the criterion variables. Third, hierarchical multiple regression results showed that negative thinking accounted for more of the significant incremental unique variance in depression, stress, anxiety, life satisfaction, anger, and happiness in order of effect size. This is also found that positive thinking do accounted for a sizable significant incremental unique variance in happiness and life satisfaction, while a very small percentage of 1% significant incremental unique variance for stress, depression, anxiety, and anger. Implications and limitations of these findings were discussed

Personality, health, and coping: A cross-national study

This study explored group and relational differences in personality, health, and coping across 189 Australian students and 243 Singaporean students. Life Orientation Test—Revised showed a one-factor structure for Australians but a two-factor structure for Singaporeans. Australians tended to be more agreeable, more conscientious, more optimistic, more satisfied with their lives, while Singaporeans tended to be more neurotic and more pessimistic. Singaporeans tended to utilize less frequent adaptive and maladaptive coping strategies. Neuroticism was a significant predictor for state-trait anxiety and stress, while unipolar optimism was a significant predictor for life satisfaction and unipolar pessimism was a significant predictor for trait anxiety for both samples. Bipolar optimism was a significant predictor for trait anxiety and life satisfaction for both samples whereas it was a significant predictor for state anxiety for the Singaporean sample. Optimists, pessimists, and neurotics in both samples tended to use different coping strategies. Limitations and implications are discussed

Personality, meta-mood experience, life satisfaction, and anxiety in Australian versus Singaporean students

This study explores two issues concerning the relationships between personality, meta-mood experience, life satisfaction, and anxiety. First, it explored the incremental value of Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience in predicting the three components of meta-mood experience (that is, attention to feelings, emotional clarity, clarity of feelings and mood repair), after controlling for demographic variables across Australia and Singapore. Second, it explored the incremental value of the three meta-mood experience components in predicting life satisfaction and anxiety, after controlling for demographic variables and personality variables across the two countries. One hundred and eighty nine tertiary students from Australia and 243 tertiary students from Singapore participated in this study. First, hierarchical regression analyses for both samples suggested that Agreeableness and Neuroticism are the two most important personality predictors of meta-mood experience, emotional attention, and emotional repair. Second, hierarchical regression analyses for both samples suggested that emotional repair was a significant predictor for life satisfaction and anxiety, even after controlling for demographic variables and personality variables. These results have implications for therapeutic interventions with life satisfaction versus anxiety