Department of Veterans Affairs Cooperative Studies Program genetic linkage study of schizophrenia: ascertainment methods and sample description

To help clarify the genetics of schizophrenia, the Department of Veterans Affairs Cooperative Studies Program has completed data collection for a genetic linkage study of schizophrenia. This article describes the methodological details of the data collection. Subsequent articles will describe the results of our genome scan, which is now in progress. The data collection protocol included the Diagnostic Interview for Genetic Studies, the Family Interview for Genetic Studies, a review of medical records, and the collection of blood for transformation into lymphoblast cell lines. Among relatives of schizophrenic probands, we assessed auditory attention and verbal memory with neuropsychological tests. Among the 166 families ascertained for the study, 143 had a single affected sib-pair, 17 had three affected siblings, one had five affected siblings and five had two sets of affected siblings. There was a total of 216 affected sib-pairs in these families. Using the n-1 rule, these families contain 188 independent affected sib-pairs.     

Evidence for an Association of the Dopamine D5 Receptor Gene on Age at Onset of Attention Deficit Hyperactivity Disorder

The purpose of this study was to determine whether the single nucleotide polymorphisms (SNPs) within candidate genes for attention deficit hyperactivity disorder (ADHD) are associated with the age at onset for ADHD. One hundred and forty-three SNPs were genotyped across five candidate genes ( DRD5 , SLC6A3 , HTR1B , SNAP25 , DRD4 ) for ADHD in 229 families with at least one affected offspring. SNPs with the highest estimated power to detect an association with age at onset were selected for each candidate gene, using a power-based screening procedure that does not compromise the nominal significance level. A time-to-onset analysis for family-based samples was performed on these SNPs to determine if an association exists with age at onset for ADHD. Seven consecutive SNPs surrounding the D5 dopamine receptor gene ( DRD5 ), were associated with the age at onset for ADHD; FDR adjusted q-values ranged from 0.008 to 0.023. This analysis indicates that individuals with the risk genotype develop ADHD earlier than individuals with any other genotype. A haplotype analysis across the 6 significant SNPs that were in linkage disequilibrium with one another, CTCATA , was also found to be significant (p-value = 0.02). We did not observe significant associations with age at onset for the other candidate loci tested. Although definitive conclusions await independent replication, these results suggest that a variant in DRD5 may affect age at onset for ADHD.     

Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients. A family study using DSM-III criteria

This report examines the risk for psychiatric illness in 723 first-degree relatives of schizophrenics and 1,056 first-degree relatives of matched surgical control patients. Diagnoses in patients and relatives were made "blind" to one another, using DSM-III criteria. Information on relatives was obtained from personal interview and/or hospital records. Results were analyzed using two levels of diagnostic certainty and with or without relatives on whom only hospital records were obtained. In all analyses, the risk for schizophrenia was significantly greater (at least 18-fold) in the relatives of schizophrenics v controls. Evidence was also found for an increased risk in relatives of schizophrenics for schizoaffective disorder, paranoid disorder, and atypical psychosis but not for unipolar disorder, anxiety disorder, or alcoholism. As defined by DSM-III, schizophrenia is a familial disorder; however, the increased risk for psychotic illness in relatives of schizophrenics does not appear to be confined to schizophrenia alone.     

Lung transplant waitlist outcomes in the United States and patient travel distance

There is a broad range of patient travel distances to reach a lung transplant hospital in the United States. Whether patient travel distance is associated with waitlist outcomes is unknown. We present a cohort study of patients listed between January 1, 2006 and May 31, 2017 using the Scientific Registry of Transplant Recipients. Travel distance was measured from the patient's permanent zip code to the transplant hospital using shared access signature URL access to Google Maps, and assessed using multivariable competing risk regression models. There were 22 958 patients who met inclusion criteria. Median travel distance was 69.7 miles. Among patients who traveled > 60 miles, 41.2% bypassed a closer hospital and sought listing at a more distant hospital. In the adjusted models, when compared to patients who traveled ≤60 miles, patients who traveled >360 miles had a 27% lower subhazard ratio (SHR) for waitlist removal (SHR 0.73, 95% confidence interval [CI]: 0.60, 0.89, P = .002), 16% lower subhazard for waitlist death (SHR 0.84; 95% CI 0.73-0.95, P = .07), and 13% increased likelihood for transplant (SHR 1.13, 95% CI: 1.07, 1.20, P < .001). Many patients bypassed the nearest transplant hospital, and longer patient travel distance was associated with favorable waitlist outcomes.     

Failure of stimulated skeletal muscle mainly contributed by passive force: an in vivo rabbit model

OBJECTIVE: To evaluate the role of active and passive muscle forces in the failure mechanism of stimulated muscle. DESIGN: An in vivo rabbit model. BACKGROUND: Eccentric contractions can result in a greater incidence of muscle injury. However, the relative role of the active and passive muscle force in the failure mechanism of the activated muscle is not well elucidated. METHODS: After anaesthesia, New Zealand white rabbits were fixed in a frame on a materials testing machine. The triceps surae muscle-tendon units were passively stretched to rupture with our without continuous nerve stimulation. The force and muscle length were simultaneously recorded. Active muscle force, passive muscle force, and ratio of the active to passive muscle were calculated and depicted against strain. RESULTS: The results showed that the mean maximal passive force of triceps surae muscle was 293.1 N at a strain of 38%. The mean peak active muscle force was 21.5 N at a strain of 21%. The ratio of active to passive muscle force reached its peak first, followed by the active muscle force, and then the passive muscle force. The ratio of active to passive muscle force at the peak total force was only 3.3%. CONCLUSIONS: The stimulated muscle can exert its maximal response at extreme physiological extension. Injury of the stimulated muscle is caused mainly by passive muscle force.     

Psychiatric epidemiology

Psychiatric epidemiology is considered one of the main scientific foundations of psychiatry. This article reviews methodological issues and major studies in psychiatric epidemiology. Methods such as measures of frequency and association are discussed. Selection, observation, and confounding, the main sources of bias in epidemiological studies, are described. Types of study designs, such as cross-sectional, cohort, and case-control, are detailed. A historical perspective of major population-based and clinical studies is presented. Major findings of the Epidemiologic Catchment Area Study and the National Comorbidity Survey are also included. Finally, future directions in the field are discussed.     

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband–parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P=1.5 × 10⁻⁴). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P=0.018) and de novo mutations (P=0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N=614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.     

Prognostic implications of paranoia and thought disorder in new onset psychosis

This study follows a group of 174 young people with new onset of schizotypal symptoms and examines factors which may lead to conversion to psychosis. These prodromal subjects were screened for symptoms and later given the Structured Clinical Interview of DSM-III-R at one year, two years and ten years post onset. We also included the Paranoia Scale of Fenigstein and Vanable and the Scale for Thought, Language and Communications of Andreasen in all interviews. Our analysis found that the addition of scales for paranoia and thought disorder enhanced prediction of conversion to psychosis and long term outcome. The early occurrence of ideas of reference and poverty of thought appear to be significant predictors of future deterioration even when considered among other high-risk variables.