Dear Students!
Our
next speaker on the 21th of March will be Tiffany Greenwood who will talk
about: "Madness and Genius".
You
will need to read his paper titled:"Genome Wide Association Study of Temperament in Bipolar Disorders Reveals Significant Associations with three Novel Loci"
Please post your comments not later than Tuesday (20th) afternoon!
Greenwood, T. A., Akiskal, H. S., Akiskal, K. K., & Kelsoe, J. R. (2012). Genome-wide association study of temperament in bipolar disorder reveals significant associations with three novel loci. Biological Psychiatry, 72(4), 303–310. https://doi.org/10.1016/j.biopsych.2012.01.018
ReplyDeleteA dysregulation of temperament has been shown to be an accurate indicator for a predisposition to bipolar spectrum disorders. A genome-wide association analysis of five temperaments (hyperthymic, dysthymic, cyclothymic, irritable, anxious) from the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A) was completed on 1263 participants with bipolar disorder and controls. Subjects were genotyped to identify possible genes associated with the predisposition to bipolar disorder subtype by indicators of temperament. Five genome-wide associations were identified; three were associated with the hyperthymic temperament, and two with irritability. The irritable temperament indicated the highest probability for genome-wide association. Results suggest emerging quantitative evidence for defining subtypes of bipolar disorder by temperament.
Question: Is a self-report questionnaire a reliable method of measure for bipolar disorder? Are individuals with BP known to be highly self-aware of symptoms?
"Genome-Wide Association Study of Temperament in Bipolar Disorder Reveals Significant Associations with Three Novel Loci", Greenwood, T. A., Akiskal, H. S., Akiskal, K. K., & Kelsoe, J. R. (2012)
ReplyDeleteThis study of Bipolar Disorder (BD) have showed three genome-wide significant p-values on chromosome 1, 12, and 22 where the irritable temperament produced the first former, and the hyperthymic temperament produced the two latters. As the literature showed that different sets of genes might be associated with each of several dimensions of temperament, the authors have explored characteristics of temperament as quantitative phenotypes that might classify sub-types of BD. And the temperament here is a heritable personality factor and establishes the baseline level of reactivity, mood, and energy of a person. The Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) is a self-report questionnaire designed to measure temperamental variations in psychiatric patients and healthy volunteers. The TEMPS-A includes a total of 109 self-rated true/false questions designed to assess hyperthymic, dysthymic, cyclothymic, irritable, and anxious temperaments with 21 questions specific to each temperament subscale and 26 for the anxious subscale. All 1566 unrelated BDI subjects of European Ancestry subjects were selected and performed at different sites across the country. The SNPs located within or near the MDM1 and FBLN1 genes support for the association in in the analysis of the hyperthymic temperament. Analysis of the irritable temperament also produced two SNPs (within the neighboring INTS7 and DTL genes) of genome wide significance. Genome wide association results for all five temperaments (hyperthymic, dysthymic, and cyclothymic, irritable, and anxious) showed that several genes of possible interest were identified, however the SNPs did not meet genome wide significance.
Questions: These subject was selected of of European Ancestry, would other ethnicity still be applied? Why BP was chosen in this research, besides several other mental disorders (why not autism)?
The authors argue that genes associated with bipolar disorder are elusive to researchers because categorical diagnostic criteria such as the DSM-V may be inadequate measures for identifying genetic risk factors. Instead, they posit that quantitative scales of traits, with normal variation in the human population, may be more informative. The authors used the TEMPS-A, a reliable scale of temperament that can quantify milder sub-clinical symptoms of bipolar disorders. They found that two of these temperament traits—irritability and hyperthymia (e.g. excessive energy & enthusiasm)—are significantly correlated with 3 different loci in the genome. The authors conclude that these loci are prime candidates for exploring genetic risk for bipolar disorder, because high scores on these traits have been found to correlate highly with a clinical diagnosis.
ReplyDeleteI am very intrigued by the use of quantitative scales rather than categorical variables as predictors of genetic risk. While categorical classification of mental disorders is often needed for access to medication and psychotherapy, a continuous spectrum of traits better reflects the nuance of complex and often socially-constructed conditions. I would be very interested to see studies that apply this methodology to developmental language disorders and language-based learning disabilities. While I am quite naive to the literature, my impression is that most studies on genetics and language focus on identifying the genes that predict a categorical diagnosis like FOXP2 and Specific Language Impairment. It would be interesting to see if there are genes that predict scaled dimensions of high and low linguistic ability—a presumably highly heritable trait.
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DeleteJessica Yoo
ReplyDeleteGenome-Wide Association Study of Temperament in Bipolar Disorder Reveals Significant Associations with Three Novel Loci (Greenwood, 2012)
Greenwood et al. explores the temperament in bipolar disorder through looking at quantitative phenotypes, since DSM-IV, a categorical system, might not be the finest system for diagnosing criteria for bipolar disorder. The study used TEMPS-A, which is a self-rating questionnaire, on 1263 bipolar subjects as this quantitative phenotype for bipolar disorder that separates five temperaments as hyperthymic, dysthymic, cyclothymic, irritable, and anxious. As the study indicated, there was a highest correlation for cyclothymic and irritable temperaments, and high correlation between dysthymic and anxious temperaments.
The irritable temperament showed to be the most significant. Is this result enough to support the debate Greenwood mentioned “whether irritable is its own temperament/ a subtype of cyclothymic temperament?” (Akiskal HS, 1998; 1992). Also, what could be some other reliable ways to measure BD through quantitative measures?
Although the genetic underpinnings of bipolar disorder (BD) remain largely ambiguous due to heterogeneity of the disorder and its representations within the population as well as small gene effects, Greenwood and colleagues propose an alternative method of investigating related genetic factors using a genome-wide association study of temperament within individuals with bipolar I subtype. Previous studies have associated dysregulations in temperament and increased risk for BD, and these investigators suggest that a variable reflecting more of a continuous distribution, such as temperament, may better identify potential subtypes of BD. The identification of subtypes could lead to more homogenous populations for genetic study, and thus improve the likelihood for identifying associated underlying genetic components. Their study revealed several significant results including two SNPs in the analysis of irritable temperament (INTS7 and DTL genes on chromosome 1) and three SNPs in the analysis of hyperthymic temperament (MDM1 and FBLN1 on chromosomes 12 and 22). Associations were also found within the other assessed temperaments (dysthymic, cyclothymic, and anxious) with the same gene, LRRC4C. Overall, this study suggests that using measures of temperament may lead to more clinically and genetically homogenous groupings of patients that may assist in the further investigation and understanding of the genetic components and clinical manifestations of BD.
ReplyDeleteQuestions: Have similar methods been used to study other conditions with similar heterogeneous presentations and small gene effects? What other variables or dimensions (for BD or other conditions) may be useful to investigate further to assist in creating more homogenous subtypes for study?
In his paper titled ‘Genome-wide association study of temperament in bipolar disorder reveals significant associations with three novel loci’, Greenwood tries to explain the role of temperament in and its correlation with bipolar disorder. Use of categorical phenotypes for genetic studies of bipolar disorder may not always yield correct results. As a result, temperament as quantitative phenotypes are used for defining subtypes of bipolar disorder. Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire or TEMPS-A was used a primary test for quantifying and assessing temperament and other bipolar symptoms. Five different types of temperaments (hyperthymic, dysthymic, cyclothymic, irritable and anxious) were used for TEMPS-A evaluation. Out of the outlined temperaments, hyperthymic temperament showed highest relation to bipolar disorder. Another interesting finding the paper highlighted was correlation between temperaments and the medications taken during clinical process. Apart from hyperthymic temperament, other previously listed temperaments showed strong relations to relapse and antidepressants. This paper thus highlights the association of temperament with bipolar disorder and its p values on chromosomes 1, 12, and 22.
ReplyDeleteAlthough attempts to identify genes responsible for bipolar disorder (BD) are underway, symptom heterogeneity and possibly inadequate diagnostic criteria, as outlined in DSM V, appear to thwart these efforts. Consequently, the aim of this article was to explore temperament as a way of defining subtypes of BD in order to create more clinically and genetically homogenous groups. The TEMPS-A questionnaire contained five temperament subtests: hyperthymic, dysthymic, cyclothymic, irritable, and anxious. These temperament scores were compared to genome-wide association analyses to identify several genes that might predispose people to BD through modulation of temperament. While high correlations were present between irritable, cyclothymic, dysthymic, and anxious temperaments, hyperthymic temperament seemed to stand independent from the other subtests. This converges with evidence from a recent study suggesting that there are two types of temperaments in BD— hyperthymic and “cyclothymic-sensitive”, characterized by rapid and unpredictable mood swings often with comorbid anxiety disorders. Hyperthymic temperament was associated with three genome-wide results, MDM1 and FBLN1. Irritable temperament was associated with INTS7 and DTL, and LRRC4C was associated with several temperament subtests, although not genome-wide significant. The authors therefore conclude that at least with respect to the hyperthymic subtest score, and possibly irritable temperament, the TEMPS-A can yield more genetically homogenous groups where implication of specific genes (e.g. FLBN1, INTS7) in BD phenotypes becomes more attainable and reliable.
ReplyDeleteWhy were control subjects not used in this study? Are these genes involved in temperament across all people (including non-BD population), or is the expression of these genes/temperaments only related to BD diagnosis/susceptibility?
Greenwood et al. (2012) suggest that deficits in the diagnostic criteria outlined by the DSM-IV, among others, could contribute to the difficulty in adequately gene mapping bipolar disorder (BD). Furthermore, the genetic heterogeneity and small gene effects of BD have also presented difficulties in this matter. This paper assessed the temperament in bipolar disorder which could help to create a baseline for identifying reactivity, mood, and energy of an individual. The Temperament Autoquestionnaire was used as a quantitative phenotype. There has been evidence that temperament in BD is associated with differences between individuals. These differences could be in response to antidepressants or rates of relapse (p.304). A genome-wide assessement was done to look at five temperaments (i.e. hyperthymic, dysthymic, cyclothymic, irritable, anxious). The hyperthymic and irritable temperaments showed genome-wide significant effects.
ReplyDeleteThe author focuses on temperament in the bipolar disorder. The genome wide association of the temperament reveals the nature of the temperaments, and can be used to classify the subtype of bipolar disorder.
ReplyDeleteTemperament is a stable personality over time using the levels of reactivity, mood and energy of a person. Usually, there are five temperaments in BDI subtype (Not clear about the difference between BDI and BDII): hyperthymic, dysthymic, cyclothymic, irritable, and anxious. People believe those different temperaments have different clinical features and courses of illness.
According to the results they found, four out of five have a significant correlations were observed. The exception is hyperthymic. It doesn’t have strong correlations like the other four temperaments. But without the table S1 in supplyment, I can’t see how much is the correlation between the temperaments and clinical characteristics.
The most interesting part is using GWA results to reveal the potential relationship in the genetics. It gives many clues to some potential gene like MDM1, FBLN1, INTS7, and DTL. The similar GWA correlation also matches other groups’ research that those four temperaments may be in the same category.
There are many details can be asked in this paper.
1. How to decide the GSA criteria. Or how does p value be calculated?
2. I didn’t understand the figure 2 in the papers.
3. How to understand that certain gene sequence will have a high p-value?