Genetic studies are under way for many complex traits, spurred by the recent feasibility of whole genome scans. Clear guidelines for the interpretation of linkage results are needed to avoid a flood of false positive claims. At the same time, an overly cautious approach runs the risk of causing true hints of linkage to be missed. We address this problem by proposing specific standards designed to maintain rigor while also promoting communication.

Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results

The measurement of meaning

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Genetics have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.

https://focus.psychiatryonline.org/doi/pdf/10.1176/foc.4.3.442

Genetic dissection of complex traits

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Genetic Dissection of Complex Traits

Humans show large differences in the preferred timing of their sleep and activity. This so-called "chronotype" is largely regulated by the circadian clock. Both genetic variations in clock genes and environmental influences contribute to the distribution of chronotypes in a given population, ranging from extreme early types to extreme late types with the majority falling between these extremes. Social (e.g., school and work) schedules interfere considerably with individual sleep preferences in the majority of the population. Late chronotypes show the largest differences in sleep timing between work and free days leading to a considerable sleep debt on work days, for which they compensate on free days. The discrepancy between work and free days, between social and biological time, can be described as 'social jetlag.' Here, we explore how sleep quality and psychological wellbeing are associated with individual chronotype and/or social jetlag. A total of 501 volunteers filled out the Munich ChronoType Questionnaire (MCTQ) as well as additional questionnaires on: (i) sleep quality (SF-A), (ii) current psychological wellbeing (Basler Befindlichkeitsbogen), (iii) retrospective psychological wellbeing over the past week (POMS), and (iv) consumption of stimulants (e.g., caffeine, nicotine, and alcohol). Associations of chronotype, wellbeing, and stimulant consumption are strongest in teenagers and young adults up to age 25 yrs. The most striking correlation exists between chronotype and smoking, which is significantly higher in late chronotypes of all ages (except for those in retirement). We show these correlations are most probably a consequence of social jetlag, i.e., the discrepancies between social and biological timing rather than a simple association to different chronotypes. Our results strongly suggest that work (and school) schedules should be adapted to chronotype whenever possible.

http://www.grp.hwz.uni-muenchen.de/pdf/wittmann_pdf/Wittmann06_Social%20Jetlag.pdf

Social Jetlag: Misalignment of Biological and Social Time

BACKGROUND: More than half of patients with depression go undetected. Self-rating scales can be useful in screening for depression, and measuring severity and treatment outcome. AIM: This study com ...

Comparison of two self-rating scales to detect depression: HADS and PHQ-9

Detection of expanded CAG repeats in bipolar affective disorder using the repeat expansion detection (RED) method.

Effect of trauma on quality of life as mediated by mental distress and moderated by coping and social support among postconflict displaced Ethiopians

https://www.jstor.org/stable/info/27641328

Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity or decrease in age at onset or both in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in different disorders. We have studied differences of age at onset and disease severity between two generations in 14 families with unilinear inheritance of bipolar affective disorder (BPAD). There was a significant difference in age at onset (p < 0.008), in episodes per year with (p < 0.006) and without (p < 0.03) lithium treatment, and in total episodes per year (p < 0.002) between generations I and II. Furthermore, there was a highly significant correlation (p < 0.001) in age at onset between generations I and II. No evidence for specific paternal or maternal inheritance was found. We found evidence of anticipation and could rule out ascertainment bias or some other artefact. Anticipation is thus an inheritance pattern in BPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in BPAD.

https://jmg.bmj.com/content/jmedgenet/31/9/686.full.pdf

Anticipation in Swedish families with bipolar affective disorder.

Genetic epidemiology deals with the interaction of environmental and genetic determinants in common diseases. Linkage analysis is an important branch of this field. The current practice of claiming linkage between two genetic loci when the maximum lod score z(theta) exceeds 3 has not received theoretical justification, whether considered as a sequential or as a fixed sample size test. Within the framework of significance testing, Wald's (1947) formulae are not applicable to allow this procedure a sequential interpretation. Considered as a fixed sample size test, we find that a chi 2 approximation would instead be very adequate. Since repeated significance testing is performed on linkage data, the nominal significance level should be more stringent for each test than the overall level. Some recent developments in group sequential trials by Pocock (1977) and in repeated significance testing by Woodroofe (1979) seem to indicate that the critical value of the maximum lod score should lie roughly between 0.9 and 3.3, depending on the maximum number of repetitions anticipated, on whether the significance level is desired to be 0.05, 0.01 or 0.001, and on whether the test is derived from a one-sided or a two-sided consideration. In terms of the group sequential approach, if a maximum of twenty repetitions is allowed, if z(theta) greater than log10 A is considered as a one-sided test and assumed to be symmetric when linkage is absent, then the type I error is approximately given by 1/A. We also treat the confidence interval approach for exclusion of unlikely recombination values.

Jayanti Chotai

Papers

Comparison of two self-rating scales to detect depression: HADS and PHQ-9

Detection of expanded CAG repeats in bipolar affective disorder using the repeat expansion detection (RED) method.

Effect of trauma on quality of life as mediated by mental distress and moderated by coping and social support among postconflict displaced Ethiopians

Anticipation in Swedish families with bipolar affective disorder.

On the lod score method in linkage analysis.