Improving estimates of genetic maps: a meta-analysis-based approach

Inaccurate genetic ( or linkage ) maps can reduce the power to detect linkage, increase type I error, and distort haplotype and relationship inference. To improve the accuracy of existing maps, I propose a meta-analysis-based method that combines independent map estimates into a single estimate of the linkage map. The method uses the variance of each independent map estimate to combine them efficiently, whether the map estimates use the same set of markers or not. As compared with a joint analysis of the pooled genotype data, the proposed method is attractive for three reasons: (1) it has comparable efficiency to the maximum likelihood map estimate when the pooled data are homogeneous; (2) relative to existing map estimation methods, it can have increased efficiency when the pooled data are heterogeneous; and (3) it avoids the practical difficulties of pooling human subjects data. On the basis of simulated data modeled after two real data sets, the proposed method can reduce the sampling variation of linkage maps commonly used in whole-genome linkage scans. Furthermore, when the independent map estimates are also maximum likelihood estimates, the proposed method performs as well as or better than when they are estimated by the program CRIMAP. Since variance estimates of maps may not always be available, I demonstrate the feasibility of three different variance estimators. Overall, the method should prove useful to investigators who need map positions for markers not contained in publicly available maps, and to those who wish to minimize the negative effects of inaccurate maps. Genet. Epidemiol . 2007. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56072/1/20221_ftp.pd

Improving Estimates of Genetic Maps: A Maximum Likelihood Approach

As a result of previous large, multipoint linkage studies there is a substantial amount of existing marker data. Due to the increased sample size, genetic maps estimated from these data could be more accurate than publicly available maps. However, current methods for map estimation are restricted to data sets containing pedigrees with a small number of individuals, or cannot make full use of marker data that are observed at several loci on members of large, extended pedigrees. In this article, a maximum likelihood (ML) method for map estimation that can make full use of the marker data in a large, multipoint linkage study is described. The method is applied to replicate sets of simulated marker data involving seven linked loci, and pedigree structures based on the real multipoint linkage study of Abkevich et al. (2003, American Journal of Human Genetics 73, 1271–1281). The variance of the ML estimate is accurately estimated, and tests of both simple and composite null hypotheses are performed. An efficient procedure for combining map estimates over data sets is also suggested.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66271/1/j.1541-0420.2006.00532.x.pd

A Pragmatic Test for Detecting Association between a Dichotomous Trait and the Genotypes of Affected Families, Controls and Independent Cases

The efficient analysis of hybrid designs [e.g., affected families, controls, and (optionally) independent cases] is attractive because it should have increased power to detect associations between genetic variants and disease. However, the computational complexity of such an analysis is not trivial, especially when the data contain pedigrees of arbitrary size and structure. To address this concern, we developed a pragmatic test of association that summarizes all of the available evidence in certain hybrid designs, irrespective of pedigree size or structure. Under the null hypothesis of no association, our proposed test statistic (POPFAM+) is the quadratic form of two correlated tests: a population-based test (e.g., wQLS), and a family-based test (e.g., PDT). We use the parametric bootstrap in conjunction with an estimate of the correlation to compute p-values, and we illustrate the potential for increased power when (1) the heritability of the trait is high; and, (2) the marker-specific association is driven by the over-representation of risk alleles in cases, and by the preferential transmission of risk alleles from heterozygous parents to their affected offspring. Based on simulation, we show that type I error is controlled, and that POPFAM+ is more powerful than wQLS or PDT alone. In a real data application, we used POPFAM+ to analyze 43 genes of a hybrid epilepsy study containing 85 affected families, 80 independent cases, 234 controls, and 118 reference samples from the International HapMap Project. The results of our analysis identified a promising epilepsy candidate gene for follow-up sequencing: malic enzyme 2 (ME2; min p < 0.0084)

Upper limits of intraocular pressure in glaucoma clinical trials

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110560/1/ceo12357.pd

Increasing the power of association studies with affected families, unrelated cases and controls

When studying the genetics of inherited diseases, researchers often collect data on affected families, unrelated cases, and healthy controls. However, the joint analysis of such heterogeneous data is difficult, and the simpler analysis of homogeneous subsets is often suboptimal. For example, while case-control tests of association are sensitive to allele frequency differences, the preferential transmission of risk alleles from heterozygous parents to their affected offspring is typically ignored. Similarly, the transmission disequilibrium test (TDT) fails to incorporate the difference in allele frequencies when testing for association. To boost the power of modern genetic studies, we propose POPFAM – a fast and efficient test of association that can accommodate large affected families, unrelated cases, and controls. We use simulations to assess the type I error and power of POPFAM across different genetic models, and minor allele frequencies. For comparison, we examine the power of competing methods: the trend test, a Wald test (equivalent to the TDT), and SCOUT. Our results show that POPFAM maintains the correct type I error, and that it is more powerful than the trend test or the TDT. It performs as well as, or better than the likelihood ratio test SCOUT, which was developed specifically for case-parent/case-control data. Furthermore, when applied to the human leukocyte antigen genotypes of 401 type 1 diabetic families, POPFAM confirmed the previously reported association between DRB1(*)03:01 and microvascular complications (p = 0.04). In general, we expect our proposed test to facilitate the identification of clinically important genomic regions, and to better inform the design of follow-up sequencing efforts

Regulation of signal transducers and activators of transcription (STATs) by effectors of adipogenesis: Coordinate regulation of STATs 1, 5A, and 5B with peroxisome proliferator-activated receptor-γ and C/AAAT enhancer binding protein-α

We have recently demonstrated that three signal transducers and activators of transcription (STAT) family members are induced during adipocyte differentiation (Stephens et al., J. Biol. Chem. 271 (1996) 10441- 10444). Since STATs 1, 5A, and 5B are induced during adipocyte differentiation, we have examined the ability of these proteins to be regulated by components of the differentiation cocktail. In addition, we have examined the effects of potent effectors of differentiation on STAT protein expression during adipogenesis. A negative effector, tumor necrosis factor-α (TNFα), and a positive effector, a thiazolidinedione, were used in these experiments. Our results demonstrate that the expression of STATs 1, 5A, and 5B is not dramatically influenced by individual components of the differentiation cocktail. However, the expression of these three STAT family members tightly correlates with lipid accumulation. Moreover, the expression of STATs 1, 5A, and 5B, but not STATs 3 and 6, are regulated in an identical fashion to both C/AAAT enhancer binding proteins α and peroxisome proliferator-activated receptor-γ by TNFα and a thiazolidinedione. Furthermore, the expression of adipocyte-expressed JAK kinases are unaffected by effectors of differentiation. These findings suggest that three STAT family members may play a role in the regulation of adipocyte gene expression

The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes

Ciliary neurotrophic factor (CNTF) is primarily known for its roles as a lesion factor released by the ruptured glial cells that prevent neuronal degeneration. However, CNTF has also been shown to cause weight loss in a variety of rodent models of obesity/type II diabetes, whereas a modified form also causes weight loss in humans. CNTF administration can correct or improve hyperinsulinemia, hyperphagia, and hyperlipidemia associated with these models of obesity. In order to investigate the effects of CNTF on fat cells, we examined the expression of CNTF receptor complex proteins (LIFR, gp130, and CNTFRα) during adipocyte differentiation and the effects of CNTF on STAT, Akt, and MAPK activation. We also examined the ability of CNTF to regulate the expression of adipocyte transcription factors and other adipogenic proteins. Our studies clearly demonstrate that the expression of two of the three CNTF receptor complex components, CNTFRα and LIFR, decreases during adipocyte differentiation. In contrast, gp130 expression is relatively unaffected by differentiation. In addition, preadipocytes are more sensitive to CNTF treatment than adipocytes, as judged by both STAT 3 and Akt activation. Despite decreased levels of CNTFRα expression in fully differentiated 3T3-L1 adipocytes, CNTF treatment of these cells resulted in a time-dependent activation of STAT 3. Chronic treatment of adipocytes resulted in a substantial decrease in fatty-acid synthase and a notable decline in SREBP-1 levels but had no effect on the expression of peroxisome proliferator-activated receptor γ, acrp30, adipocyte-expressed STAT proteins, or C/EBPa. However, CNTF resulted in a significant increase in IRS-1 expression. CNTFRα receptor expression was substantially induced in the fat pads of four rodent models of obesity/type II diabetes as compared with lean littermates. Moreover, we demonstrated that CNTF can activate STAT 3 in adipose tissue and skeletal muscle in vivo. In summary, CNTF affects adipocyte gene expression, and the specific receptor for this cytokine is induced in rodent models of obesity/type II diabetes

Sexually Transmitted Infections among HIV-1-Discordant Couples

INTRODUCTION:More new HIV-1 infections occur within stable HIV-1-discordant couples than in any other group in Africa, and sexually transmitted infections (STIs) may increase transmission risk among discordant couples, accounting for a large proportion of new HIV-1 infections. Understanding correlates of STIs among discordant couples will aid in optimizing interventions to prevent HIV-1 transmission in these couples. METHODS:HIV-1-discordant couples in which HIV-1-infected partners were HSV-2-seropositive were tested for syphilis, chlamydia, gonorrhea, and trichomoniasis, and HIV-1-uninfected partners were tested for HSV-2. We assessed sociodemographic, behavioral, and biological correlates of a current STI. RESULTS:Of 416 couples enrolled, 16% were affected by a treatable STI, and among these both partners were infected in 17% of couples. A treatable STI was found in 46 (11%) females and 30 (7%) males. The most prevalent infections were trichomoniasis (5.9%) and syphilis (2.6%). Participants were 5.9-fold more likely to have an STI if their partner had an STI (P<0.01), and STIs were more common among those reporting any unprotected sex (OR = 2.43; P<0.01) and those with low education (OR = 3.00; P<0.01). Among HIV-1-uninfected participants with an HSV-2-seropositive partner, females were significantly more likely to be HSV-2-seropositive than males (78% versus 50%, P<0.01). CONCLUSIONS:Treatable STIs were common among HIV-1-discordant couples and the majority of couples affected by an STI were discordant for the STI, with relatively high HSV-2 discordance. Awareness of STI correlates and treatment of both partners may reduce HIV-1 transmission. TRIAL REGISTRATION:ClinicalTrials.gov NCT00194519

Parkfield earthquakes of June 27-29, 1966, Monterey and San Luis Obispo Counties, California—Preliminary report

Two earthquakes, M = 5.3 and 5.5, shook the Parkfield area in southern Monterey County, California, at 0409:56.5 and 0426:13.8 GMT, 28 June 1966. They were preceded by foreshocks on the same day at 0100 and 0115. A third shock, M = 5.0, occurred in the same area at 1953:26.2 on 29 June. The earthquakes were followed by a heavy sequence of aftershocks with epicenters along the San Andreas fault zone extending for about 15 miles southward beyond Cholame in San Luis Obispo County. A P-wave first-motion fault plane solution shows strike of vertical fault plane is N 33°W, coinciding with a surface zone of en echelon fault fractures in the pattern characteristic of right-lateral, strike-slip movement. The motion appears to have an upward component on the west side, at about 20° from pure strike slip. Extensive instrumentation within a few miles of the epicentral district gave unusually complete records from foreshock to aftershock sequence. A strong-motion instrument in the fault zone near Cholame recorded the unusually high horizontal acceleration of 0.5 g. The epicentral region of the earthquakes is on a known active segment of the San Andreas fault. Earthquakes in 1901, 1922, and 1934 in this region were also accompanied by surface faulting. On the published State geologic map, scale 1:250,000, the San Andreas fault zone shows a braided pattern of several branching en echelon major faults. Topographic forms, typical of the features of rift valleys, testify to the recency of fault movements. Small right-lateral surficial displacements had been recognized prior to the late June earthquakes in at least three places on the Parkfield-Cholame trace of the fault. Similar creep, or slippage, has continued since the earthquakes. Extensive nets of survey markers installed by 30 June across the active fault trace had recorded slippage as great as 0.1 inch per day by 12 July. The fault trace associated with the earthquakes is principally in alluvium of unknown depth in Cholame Valley, apparently a faulted graben within the San Andreas fault zone. Under a blanket of Tertiary and Quaternary sedimentary rocks in this part of the southern Coast Ranges, the great fault separates Jurassic-Cretaceous granitic and metamorphic rocks in the western block from Late Jurassic eugeosynclinal sedimentary and volcanic rocks of the Franciscan Formation in the eastern block. In spite of the large horizontal acceleration recorded near the fault, very little building damage occurred in this sparsely populated region. Small concrete and steel bridges in, and adjacent to the fault trace, did not have their structural strength impaired

A central role for dityrosine crosslinking of Amyloid-β in Alzheimer’s disease

Background Alzheimer’s disease (AD) is characterized by the deposition of insoluble amyloid plaques in the neuropil composed of highly stable, self-assembled Amyloid-beta (Aβ) fibrils. Copper has been implicated to play a role in Alzheimer’s disease. Dimers of Aβ have been isolated from AD brain and have been shown to be neurotoxic. Results We have investigated the formation of dityrosine cross-links in Aβ42 formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress with elevated copper and shown that dityrosine can be formed in vitro in Aβ oligomers and fibrils and that these links further stabilize the fibrils. Dityrosine crosslinking was present in internalized Aβ in cell cultures treated with oligomeric Aβ42 using a specific antibody for dityrosine by immunogold labeling transmission electron microscopy. Results also revealed the prevalence of dityrosine crosslinks in amyloid plaques in brain tissue and in cerebrospinal fluid from AD patients. Conclusions Aβ dimers may be stabilized by dityrosine crosslinking. These results indicate that dityrosine cross-links may play an important role in the pathogenesis of Alzheimer’s disease and can be generated by reactive oxygen species catalyzed by Cu2+ ions. The observation of increased Aβ and dityrosine in CSF from AD patients suggests that this could be used as a potential biomarker of oxidative stress in AD