Population Genetics Identifies Challenges in Analyzing Rare Variants

Geneticists have, for years, understood the nature of genome‐wide association studies using common genomic variants. Recently, however, focus has shifted to the analysis of rare variants. This presents potential problems for researchers, as rare variants do not always behave in the same way common variants do, sometimes rendering decades of solid intuition moot. In this paper, we present examples of the differences between common and rare variants. We show why one must be significantly more careful about the origin of rare variants, and how failing to do so can lead to highly inflated type I error. We then explain how to best avoid such concerns with careful understanding and study design. Additionally, we demonstrate that a seemingly low error rate in next‐generation sequencing can dramatically impact the false‐positive rate for rare variants. This is due to the fact that rare variants are, by definition, seen infrequently, making it hard to distinguish between errors and real variants. Compounding this problem is the fact that the proportion of errors is likely to get worse, not better, with increasing sample size. One cannot simply scale their way up in order to solve this problem. Understanding these potential pitfalls is a key step in successfully identifying true associations between rare variants and diseases.     

Vitamin D receptor genotype and risk of osteoporotic hip fracture in elderly women of Utah: an effect modified by parity

Introduction The associations between vitamin D receptor (VDR) Bsm I and Fok I genotypes, parity, and risk of osteoporotic hip fracture were evaluated in a statewide population-based case-control study in Utah.Methods Women age 50–89 years with hip fracture (n=882) were ascertained via surveillance of 18 Utah hospitals from 1997 to 2001. Age-matched controls were randomly selected (n=897). Participants were interviewed in their homes, and blood samples were collected for genotyping.Results In logistic regression analyses that controlled for multiple confounders, Bsm I VDR genotype but not Fok I genotype was associated with risk of osteoporotic hip fracture (OR bb vs. BB genotype: 0.68; 95% CI: 0.50, 0.95). In similar analyses, no overall association was observed between parity status and risk of osteoporotic hip fracture. However, the effect of VDR genotype was modified by parity status. Among nulliparous women (n=140), Bsm I genotype was not associated with risk of hip fracture (OR bb vs. BB: 0.82; 95% CI: 0.28, 2.4); among primiparous women (n=133), bb genotype was associated with increased risk of hip fracture (OR bb vs. BB: 3.30; 95% CI: 0.96, 11.29); among multiparous women (n=1,400), bb genotype was associated with decreased risk of hip fracture (OR bb vs. BB: 0.59; 95% CI: 0.42, 0.84).Conclusion VDR Bsm I genotype was associated with risk of hip fracture in Utah women, and this effect was modified by parity status. Hormonal or lifestyle factors related to parity may underlie this interaction.     

“Panic-like” symptomatology in schizophrenic and schizoaffective patients with postpsychotic depression: Observations and implications

Approximately one quarter of a series of 45 schizophrenic and schizoaffective patients with operationally diagnosed episodes of postpsychotic depression were also found to have anxiety symptoms consistent with the panic-attack syndrome. The incidence of such attacks was distributed across all demographic groups. Heuristic and treatment implications of this observation are considered.     

Residence differences in the health status of elders.

Using data from the 1984 Supplement on Aging to the National Health Interview Survey, this study examined residential differences on a selected group of health status measures among persons 65 years of age and older (N = 11,497). Mean values on indicators of health and impairment for each of the residence categories were examined before and after adjusting for distributional differences in background and demographic characteristics which are associated with both health and residence. Three important conclusions emerged from the analysis: (1) health status does not vary with residence in a unitary fashion; (2) the relationship between residence and health status does not appear to fall along a straightforward rural-urban continuum; and (3) there is both diversity in, and a general patterning of, the significant relationships between health and residence with the extremes of health status located in the rural categories.     

Academic,community and state mental health program collaboration: The Oregon experience

The authors review the relationship that has evolved over the years between the Department of Psychiatry at Oregon Health Sciences University and Oregon's community and state mental health programs. They describe the compatibility that exists between the basic requirements of academic psychiatry departments and public mental health programs and demonstrate how these organizations have been able to fulfill one another's needs in Oregon. Specific examples of successful collaborations in the areas of education, administration, research, and service are presented to illustrate how relationships that have been designed to meet specific requirements of one organization can fulfill many requirements of both. Suggestions are provided for those organizations contemplating similar collaborative endeavors.     

Luteinizing hormone releasing hormone analogue therapy for central precocious puberty. Long-term effect on somatic growth, bone maturation, and predicted height

The long-acting analogue of luteinizing hormone releasing hormone, D-Trp6-Pro9-NEt-LHRH (LHRHa), is effective in the short-term treatment of central precocious puberty. We report the results of two to four years of LHRHa therapy in 27 children with this disorder. Secondary sex characteristics regressed in most patients. Sex steroid levels and basal and LHRH-stimulated gonadotropin levels remained suppressed compared with pretreatment values. Linear growth rates decreased from 11.0 +/- 0.8 (SEM) cm/yr before treatment to 5.7 +/- 0.4 cm/yr at two years of treatment and 3.7 +/- 0.7 cm/yr at four years of treatment. Predicted heights by the Bayley-Pinneau method increased from 156.4 +/- 2.0 cm before treatment to 162.3 +/- 2.3 cm at two years and 163.4 +/- 2.4 cm at three years. Five patients treated for four years had a mean increase in predicted height of 5.5 cm. To date no adverse effects have been observed. However, the ultimate safety of this analogue is not known. We conclude that LHRHa appears to be an effective long-term therapy for central precocious puberty.     

Predictors of self-reported problems of confusion among the aged.

Responses to questions on the 1984 Supplement on Aging to the National Health Interview Survey (NHIS) about the experience of personal confusion revealed that two-thirds of those interviewed reported never having an episode of confusion during the preceding year. Of those who reported episodes, fewer than one in five said they were happening with increased frequency. The many meanings of confusion found in the literature prompted a modest local study of what respondents understood by the term when asked the NHIS questions. Of those who admitted occasional confusion, almost two-thirds gave definitions that included memory loss or forgetfulness. Consequently, increased frequency of memory problems and difficulty in remembering were included with other variables in the analyses to identify significant predictors. They emerged the single best predictors of how often a respondent reported getting confused. Others were change in health status, number of functional limitations, educational attainment, and vision problems.