MI-GWAS: a SAS platform for the analysis of inherited and maternal genetic effects in genome-wide association studies using log-linear models

<p>Abstract</p> <p>Background</p> <p>Several platforms for the analysis of genome-wide association data are available. However, these platforms focus on the evaluation of the genotype inherited by affected (i.e. case) individuals, whereas for some conditions (e.g. birth defects) the genotype of the mothers of affected individuals may also contribute to risk. For such conditions, it is critical to evaluate associations with both the maternal and the inherited (i.e. case) genotype. When genotype data are available for case-parent triads, a likelihood-based approach using log-linear modeling can be used to assess both the maternal and inherited genotypes. However, available software packages for log-linear analyses are not well suited to the analysis of typical genome-wide association data (e.g. including missing data).</p> <p>Results</p> <p>An integrated platform, Maternal and Inherited Analyses for Genome-wide Association Studies <b>(</b>MI-GWAS) for log-linear analyses of maternal and inherited genetic effects in large, genome-wide datasets, is described. MI-GWAS uses SAS and LEM software in combination to appropriately format data, perform the log-linear analyses and summarize the results. This platform was evaluated using existing genome-wide data and was shown to perform accurately and relatively efficiently.</p> <p>Conclusions</p> <p>The MI-GWAS platform provides a valuable tool for the analysis of association of a phenotype or condition with maternal and inherited genotypes using genome-wide data from case-parent triads. The source code for this platform is freely available at <url>http://www.sph.uth.tmc.edu/sbrr/mi-gwas.htm</url>.</p

Fitting model of ABR age dependency in a clinical population of normal hearing children

The purpose of this study was to present a simple and powerful fitting model that describes age-dependent changes of auditory brainstem responses (ABR) in a clinical population of normal hearing children. A total of 175 children (younger than 200 weeks postconceptional age) were referred for audiologic assessment with normal ABR results. ABR parameters of normal hearing children between 2003 and 2008 were included. The results of the right ears recorded at 90 dB nHL were analyzed. A simple and accurate fitting model was formulated based on these data. A very similar age-dependent effect was found for peaks III and V, and I–III and I–V intervals; latencies decrease as postconceptional age increases. It shows that the total age-dependent effect will be completed after 1.5–2 years. The age-dependent effect can be modeled by a relatively simple and accurate exponential function. This fitting model can be easily implemented to analyze ABR results of infants in daily clinical practice. We speculate about the underlying physiological processes

Analysis of sequence variations in the suppressor of cytokine signaling (SOCS)-3 gene in extremely obese children and adolescents

BACKGROUND: The suppressor of cytokine signaling (SOCS)-3 is a negative feedback regulator of cytokine signaling and also influences leptin signaling. We investigated association of variations in the coding sequence and promoter region of SOCS3 with extreme obesity in German children and adolescents. METHODS: An initial screen for sequence variations in 181 extremely obese children and adolescents and 188 healthy underweight adults revealed two previously reported single nucleotide polymorphisms (SNPs) in the SOCS3 5' region: -1044 C>A (numbering refers to bases upstream of ATG in exon 2) within a predicted STAT3 binding element and -920 C>A (rs12953258, for numbering, see above). RESULTS: We did not detect significant differences in allele or genotype frequencies for any of these SNPs between the analysed study groups (all nominal p > 0.2). In addition, we performed a pedigree transmission disequilibrium test (PDT) for the SNP -1044 C>A in families comprising 703 obese children and adolescents, 281 of their obese siblings and both biological parents. The PDT revealed no transmission disequilibrium (nominal p > 0.05). CONCLUSION: In conclusion, our data do not suggest evidence for a major role of the respective SNPs in SOCS3 in the pathogenesis of extreme obesity in our study groups

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Pesticide Leaching from Agricultural Fields with Ridges and Furrows

In the evaluation of the risk of pesticide leaching to groundwater, the soil surface is usually assumed to be level, although important crops like potato are grown on ridges. A fraction of the water from rainfall and sprinkler irrigation may flow along the soil surface from the ridges to the furrows, thus bringing about an extra load of water and pesticide on the furrow soil. A survey of the literature reveals that surface-runoff from ridges to furrows is a well-known phenomenon but that hardly any data are available on the quantities of water and pesticide involved. On the basis of a field experiment with additional sprinkler irrigation, computer simulations were carried out with the Pesticide Emission Assessment at Regional and Local scales model for separate ridge and furrow systems in a humic sandy potato field. Breakthrough curves of bromide ion (as a tracer for water flow) and carbofuran (as example pesticide) were calculated for 1-m depth in the field. Bromide ion leached comparatively fast from the furrow system, while leaching from the ridge system was slower showing a maximum concentration of about half of that for the furrow system. Carbofuran breakthrough from the furrow system began about a month after application and increased steadily to substantial concentrations. Because the transport time of carbofuran in the ridge soil was much longer, no breakthrough occurred in the growing season. The maximum concentration of carbofuran leaching from the ridge–furrow field was computed to be a factor of six times as high as that computed for the corresponding level field. The study shows that the risk of leaching of pesticides via the furrow soil can be substantially higher than that via the corresponding level field soil

708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects:analysis for association with psychiatric disorder and cognitive traits

A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of &lt;1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10-5, OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies. © 2014 Macmillan Publishers Limited

Reading during the composition of multi-sentence texts: an eye-movement study

Writers composing multi-sentence texts have immediate access to a visual representation of what they have written. Little is known about the detail of writers’ eye movements within this text during production. We describe two experiments in which competent adult writers’ eye-movements were tracked while performing short expository writing tasks. These are contrasted with conditions in which participants read and evaluated researcher-provided texts. Writers spent a mean of around 13% of their time looking back into their text. Initiation of these look-back sequences was strongly predicted by linguistically important boundaries in their ongoing production (e.g., writers were much more likely to look back immediately prior to starting a new sentence). 36% of look-back sequences were associated with sustained reading and the remainder with less patterned forward and backward saccades between words ("hopping"). Fixation and gaze durations and the presence of word-length effects suggested lexical processing of fixated words in both reading and hopping sequences. Word frequency effects were not present when writers read their own text. Findings demonstrate the technical possibility and potential value of examining writers’ fixations within their just-written text. We suggest that these fixations do not serve solely, or even primarily, in monitoring for error, but play an important role in planning ongoing production

The Prevalence of the Term Subluxation in Chiropractic Degree Program Curricula Throughout the World

Background: The subluxation construct generates debate within and outside the profession. The International Chiropractic Education Collaboration, comprised of 10 chiropractic programs outside of North America, stated they will only teach subluxation in a historical context. This research sought to determine how many chiropractic institutions worldwide still use the term in their curricula and to expand upon the previous work of Mirtz & and Perle. Methods: Forty-six chiropractic programs, 18 United States (US) and 28 non-US, were identified from the World Federation of Chiropractic Educational Institutions list. Websites were searched by multiple researchers for curricular information September 2016–September 2017. Some data were not available on line, so email requests were made for additional information. Two institutions provided additional information. The total number of mentions of subluxation in course titles, technique course (Tech) descriptions, principles and practice (PP) descriptions, and other course descriptions were reported separately for US and non-US institutions. Means for each category were calculated. The number of course titles and descriptions using subluxation was divided by the total number of courses for each institution and reported as percentages. Results: Means for use of subluxation by US institutions were: Total course titles = .44; Tech = 3.83; PP = 1.50; other = 1.16. For non-US institutions, means were: Total course titles = .07; Tech = .27; PP = .44; other = 0. The mean total number of mentions was 6.94 in US vs. 0.83 in non-US institutions. Similarly, the mean course descriptions was 6.50 in US vs. 0.72 in non-US institutions. Conclusions: The term subluxation was found in all but two US course catalogues. The use of subluxation in US courses rose from a mean of 5.53 in 2011 to 6.50 in 2017. US institutions use the term significantly more frequently than non-US. Possible reasons for this were discussed. Unscientific terms and concepts should have no place in modern education, except perhaps in historical context. Unless these outdated concepts are rejected, the chiropractic profession and individual chiropractors will likely continue to face difficulties integrating with established health care systems and attaining cultural authority as experts in conservative neuro-musculoskeletal health care.https://doi.org/10.1186/s12998-018-0191-

Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation

<p>Abstract</p> <p>Background</p> <p>The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC).</p> <p>Results</p> <p>This study used a computational model of the PFC to investigate the dynamics of the PFC circuit with and without chandelier cells and other GABAergic interneurons. The inhibition by GABAergic interneurons other than chandelier cells effectively regulated the PFC activity with rather low or modest levels of dopaminergic neurotransmission. This activity of the PFC is associated with normal cognitive functions and has an inverted-U shaped profile of dopaminergic modulation. In contrast, the chandelier cell-type inhibition affected only the PFC circuit dynamics in hyperdopaminergic conditions. Reduction of chandelier cell-type inhibition resulted in bistable dynamics of the PFC circuit, in which the upper stable state is associated with a hyperactive mode. When both types of inhibition were reduced, this hyperactive mode and the conventional inverted-U mode merged.</p> <p>Conclusion</p> <p>The results of our simulation suggest that, in schizophrenia, a reduction of GABAergic inhibition increases vulnerability to psychosis by (i) producing the hyperactive mode of the PFC with hyperdopaminergic neurotransmission by dysfunctional chandelier cells and (ii) increasing the probability of the transition to the hyperactive mode from the conventional inverted-U mode by dysfunctional GABAergic interneurons.</p

Pattern Classification of Working Memory Networks Reveals Differential Effects of Methylphenidate, Atomoxetine, and Placebo in Healthy Volunteers

Stimulant and non-stimulant drugs can reduce symptoms of attention deficit/hyperactivity disorder (ADHD). The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for ADHD treatment, but their differential effects on human brain function remain unclear. We combined event-related fMRI with multivariate pattern recognition to characterize the effects of MPH and ATX in healthy volunteers performing a rewarded working memory (WM) task. The effects of MPH and ATX on WM were strongly dependent on their behavioral context. During non-rewarded trials, only MPH could be discriminated from placebo (PLC), with MPH producing a similar activation pattern to reward. During rewarded trials both drugs produced the opposite effect to reward, that is, attenuating WM networks and enhancing task-related deactivations (TRDs) in regions consistent with the default mode network (DMN). The drugs could be directly discriminated during the delay component of rewarded trials: MPH produced greater activity in WM networks and ATX produced greater activity in the DMN. Our data provide evidence that: (1) MPH and ATX have prominent effects during rewarded WM in task-activated and -deactivated networks; (2) during the delay component of rewarded trials, MPH and ATX have opposing effects on activated and deactivated networks: MPH enhances TRDs more than ATX, whereas ATX attenuates WM networks more than MPH; and (3) MPH mimics reward during encoding. Thus, interactions between drug effects and motivational state are crucial in defining the effects of MPH and ATX