A serious problem with case-control studies is that population subdivision, recent admixture and sampling variance can lead to spurious associations between a phenotype and a marker locus, or indeed may mask true associations. This is also a concern in therapeutics since drug response may differ by ethnicity. Population stratification can occur if cases and controls have different frequencies of ethnic groups or in admixed populations, different fractions of ancestry, and when phenotypes of interest such as disease, drug response or drug metabolism, also differ between ethnic groups. Although most genetic variation is inter-individual, there is also significant inter-ethnic variation. The International HapMap Project has provided allele frequencies for approximately three million single nucleotide polymorphisms (SNPs) in Africans, Europeans and East Asians. SNP variation is greatest in Africans. Statistical methods for the detection and correction of population stratification, principally Structured Association and Genomic Control, have recently become freely available. These methods use marker loci spread throughout the genome that are unlinked to the candidate locus to estimate the ancestry of individuals within a sample, and to test for and adjust the ethnic matching of cases and controls. To date, few case-control association studies have incorporated testing for population stratification. This paper will focus on the debate about the quantity and methods for selection of highly informative marker loci required to characterize populations that vary in substructure or the degree of admixture, and will discuss how these theoretically desirable approaches can be effectively put into practice.
A rhodium(I)-catalyzed highly enantioselective ring-opening and isomerization of cyclobutanols has been developed. The reaction provides a mild, atom-economical, and redox-neutral approach for the synthesis of chiral acyclic ketones bearing a β-tertiary stereocenter. Excellent enantioselectivities and high yields can be achieved using cyclobutanols with alkoxy substituents at the C3 position. Mechanistic studies reveal that cyclobutanol only undergoes intramolecular hydrogen migration, and the formation of a (Z)-unsaturated ketone intermediate is crucial for achieving high enantioselectivity.
Hidden hearing refers to the functional deficits in hearing without deterioration in hearing sensitivity. This concept is proposed based upon recent finding of massive noise-induced damage on ribbon synapse between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in the cochlea without significant permanent threshold shifts (PTS). Presumably, such damage may cause coding deficits in auditory nerve fibers (ANFs). However, such deficits had not been detailed except that a selective loss of ANFs with low spontaneous rate (SR) was reported. In the present study, we investigated the dynamic changes of ribbon synapses and the coding function of ANF single units in one month after a brief noise exposure that caused a massive damage of ribbon synapses but no PTS. The synapse count and functional response measures indicates a large portion of the disrupted synapses were re-connected. This is consistent with the fact that the change of SR distribution due to the initial loss of low SR units is recovered quickly. However, ANF coding deficits were developed later with the re-establishment of the synapses. The deficits were found in both intensity and temporal processing, revealing the nature of synaptopathy in hidden hearing loss.
The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing controversy; meta-analysis of studies across 3 decades shows an association between rs1800497 and AUD, but genome-wide analyses have detected no role for rs1800497 in any phenotype. No evidence has emerged that rs1800497, which is located inANKK1, perturbs the expression or function ofDRD2.
Objective
To resolve contradictions in previous studies by identifying hidden confounders and assaying for functional effects of rs1800497 and other loci in theDRD2region.
Data Sources
PubMed (882 studies), Embase (1056 studies), and Web of Science (501 studies) databases were searched through August 2018. Three clinical populations—Finnish, Native American, and African American participants—were genotyped for 208 to 277 informative single-nucleotide polymorphisms (SNPs) across theDRD2region to test the associations of SNPs in this region with AUD.
Study Selection
Eligible studies had diagnosis of AUD made by accepted criteria, reliable genotyping methods, sufficient genotype data to calculate odds ratios and 95% CIs, and availability of control allele frequencies or genotype frequencies.
Data Extraction and Synthesis
After meta-analysis of 62 studies, metaregression was performed to detect between-study heterogeneity and to explore the effects of moderators, including deviations of cases and controls from allele frequencies in large population databases (ExAC and 1000 Genomes). Linkage to AUD and the effect on gene expression of rs1800497 were evaluated in the context of other SNPs in theDRD2region. Data analysis was performed from August 2018 to March 2019. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline.
Main Outcomes and Measures
The effects of rs1800497 and other SNPs in theDRD2region on gene expression were measured in human postmortem brain samples via differential allelic expression and evaluated in other tissues via publicly available expression quantitative locus data.
Results
A total of 62 studies ofDRD2and AUD with 16 294 participants were meta-analyzed. The rs1800497 SNP was associated with AUD (odds ratio, 1.23; 95% CI, 1.14-1.31;P < .001). However, the association was attributable to spuriously low allele frequencies in controls in positive studies, which also accounted for some between-study heterogeneity (I2 = 43%; 95% CI, 23%-58%;Q61 = 107.20). Differential allelic expression of human postmortem brain and analysis of expression quantitative loci in public data revealed that a cis-acting locus or loci perturb theDRD2transcript level; however, rs1800497 does not and is not in strong disequilibrium with such a locus. Across theDRD2region, other SNPs are more strongly associated with AUD than rs1800497, although noDRD2SNP was significantly associated in these 3 clinical samples.
Conclusions and Relevance
In this meta-analysis, the significant association ofDRD2with AUD was reassessed. TheDRD2association was attributable to anomalously low control allele frequencies, not function, in positive studies. For genetic studies, statistical replication is not verification.
A salient effect of addictive drugs is to hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Reduced dopamine type 2 receptor availability in the striatum is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences etiologic for this disorder. Here, we sought to identify gene expression changes attributable to innate low expression of the
Abstract Hearing loss has been associated with cognitive decline in the elderly and is considered to be an independent risk factor for dementia. One of the most common causes for acquired sensorineural hearing loss is exposure to excessive noise, which has been found to impair learning ability and cognitive performance in human subjects and animal models. Noise exposure has also been found to depress neurogenesis in the hippocampus. However, the effect is mainly attributed to the oxidant stress of noise on the cognitive brain. In the present study, young adult CBA/CAJ mice (between 1.5 and 2 months of age) were briefly exposed a high sound level to produce moderate-to-severe hearing loss. In both the blood and hippocampus, only transient oxidative stress was observed after noise exposure. However, a deficit in spatial learning/memory was revealed 3 months after noise exposure. Moreover, the deficit was correlated with the degree of hearing loss and was associated with a decrease in neurogenesis in the hippocampus. We believe that the observed effects were likely due to hearing loss rather than the initial oxidant stress, which only lasted for a short period of time.
To investigate the morbidity of congenital hearing impairment among high-risk newborns and the relevant pathogenic factors.Initial screening of hearing by otoacoustic emission (OAE) was conducted among 208 high-risk newborns, 130 males and 78 females after they were born and the second screening was conducted by OAE was conducted 42 days after those with positive results were examined by auditary brainstem response (ABR).All of the 208 newborns received the initial screening with a screening rate of 100%, and 130 newborns received the second screening with a screening rate of 62.5%. The positive rates in the initial screening and second screening were 34.61% and 7.14% respectively. Six newborns were examined by ABR and 2 of them were diagnoses as with hearing impairment with a prevalence rate of 1.78%. The factors, such as sex, age, and Apgar score affected the initial screening results.The most proper time for initial hearing screening is around the 42nd day after birth. High-risk newborns should receive regular test even though they pass the initial screening. A special follow-up system should be constructed for the high-risk newborns.
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