Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci.

BACKGROUND: Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes. METHOD: We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential. RESULTS: Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing. CONCLUSIONS: The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk.

Meta-analysis of genome-wide association studies of anxiety disorders.

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Transferência de imunidade passiva em cordeiros de corte manejados extensivamente em clima tropical / Passive transfer of immunity in meat lambs reared in the tropics on extensive management

Aspectos relacionados à transferência de imunidade passiva (TIP) foram estudados em 290 cordeiros recém-nascidos, cruzas Texel, manejados extensivamente em contato permanente com as suas mães, e criados em clima tropical. Amostras de sangue foram colhidas dos cordeiros uma única vez entre 24 e 36 horas de vida para obtenção do soro sanguíneo. Foram determinadas a atividade da gama glutamiltransferase e as concentrações de proteínas totais por refratometria e colorimetria, de albumina, alfa, beta e gamaglobulinas por eletroforese e de IgG estimada pela turvação pelo sulfato de zinco. Os cordeiros foram agrupados de acordo com o sexo, o número de partos das ovelhas, o escore de condição corporal (ECC) da ovelha, o número de cordeiros nascidos, o peso e a vitalidade ao nascimento. Os fatores de risco para a ocorrência de falha na transferência de imunidade passiva (FTIP) foram identificados e a sua associação com a mortalidade de cordeiros foi testada. Foram estabelecidas correlações entre as variáveis estudadas. A TIP não foi influenciada pelo sexo, pelo número de partos ou pelo ECC das ovelhas. Houve diferenças entre os cordeiros únicos e gêmeos e entre os que nasceram com peso ≥3 kg e < 3 kg. A FTIP foi pouco frequente (12,4%), mais provável em gêmeos (p=0,026) e em cordeiros leves (p<0,001) e esteve fortemente associada com a mortalidade dos cordeiros até os 60 dias de vida (p<0,001). A taxa de mortalidade geral foi de 11,3%; e 30,5% dos cordeiros com FTIP morreram, quase todos no primeiro mês de vida. A concentração de proteína total determinada por refratometria se correlacionou (p<0,001) com as concentrações de gamaglobulinas (r=0,816) e de IgG (r=0,810) e o valor crítico ≤ 5,0g/dL para a proteína total pode ser admitido como indicador de FTIP...

Aspects related to passive transfer of immunity (PTI) were studied in 290 newborn lambs, crosses of Texel, kept with their mothers on extensive management intropical weather. Blood samples were taken between 24 and 36 hours of life. Serum gamma glutamyltransferase activity, total protein concentration, measured by refractometry and colorimetry, albumin, alfa, beta and gammaglobulins concentrations, measured by agarose gel electrophoresis, and IgG concentration estimated by the zinc sulphate turbidity test were determined. The lambs were grouped according to sex, ewe number of parturitions and body condition scoring, number of lambs born, birth weight and vitality. The risk factors for failure of passive transfer of immunity (FPT) were identified and the association with lamb mortality was tested. Correlations between variables were established. There was no effect of sex, number of parturitions of ewes and ewe body condition scoring on PTI of lambs. However there were differences between singles and twins and between lambs born with good or lightweight (<3 kg). The FPT was infrequent (12.4%), more likely in twins (p=0.026) and in lightweight lambs (p<0.001), and was strongly associated with lamb deaths up to 60 days of age (p<0.001). The global mortality rate was 11.3%; and 30.5% of the lambs with FPT died, almost all in their first month of life. The total protein concentration, measured by refractometry, was correlated (p<0.001) with gammaglobulins (r=0.816) and IgG (r=0.810); and values < 5.0g/dL can be accepted for the diagnosis of FPT. Under tropical weather conditions FTP must be considered infrequent in crossbred meat lambs. However the surveillance and care must be intensified with twins and lambs with low birth weight.

Tarsal tunnel syndrome.

Most authors agree that surgical decompression is the treatment of choice for tarsal tunnel syndrome when conservative treatment fails. Overall, the results of surgical treatment for tarsal tunnel have been favorable. Studies have shown that surgical release improves or resolves symptoms of tarsal tunnel syndrome in 85% to 90% of cases.

Nurses' responses to moral dilemmas.

Using six typical dilemma situations a study testing the morality and reasons for the reactions of subjects was conducted and the responses investigated.