Genome-wide screen to identify genetic loci associated with cognitive decline in late-life depression.

OBJECTIVE: This study sought to conduct a comprehensive search for genetic risk of cognitive decline in the context of geriatric depression. DESIGN: A genome-wide association study (GWAS) analysis in the Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. SETTING: Longitudinal, naturalistic follow-up study. PARTICIPANTS: Older depressed adults, both outpatients and inpatients, receiving care at an academic medical center. MEASUREMENTS: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery was administered to the study participants at baseline and a minimum of twice within a subsequent 3-year period in order to measure cognitive decline. A GWAS analysis was conducted to identify genetic variation that is associated with baseline and change in the CERAD Total Score (CERAD-TS) in NCODE. RESULTS: The GWAS of baseline CERAD-TS revealed a significant association with an intergenic single-nucleotide polymorphism (SNP) on chromosome 6, rs17662598, that surpassed adjustment for multiple testing (p = 3.7 × 10-7; false discovery rate q = 0.0371). For each additional G allele, average baseline CERAD-TS decreased by 8.656 points. The most significant SNP that lies within a gene was rs11666579 in SLC27A1 (p = 1.1 × 10-5). Each additional copy of the G allele was associated with an average decrease of baseline CERAD-TS of 4.829 points. SLC27A1 is involved with processing docosahexaenoic acid (DHA), an endogenous neuroprotective compound in the brain. Decreased levels of DHA have been associated with the development of Alzheimer's disease. The most significant SNP associated with CERAD-TS decline over time was rs73240021 in GRXCR1 (p = 1.1 × 10-6), a gene previously linked with deafness. However, none of the associations within genes survived adjustment for multiple testing. CONCLUSIONS: Our GWAS of cognitive function and decline among individuals with late-life depression (LLD) has identified promising candidate genes that, upon replication in other cohorts of LLD, may be potential biomarkers for cognitive decline and suggests DHA supplementation as a possible therapy of interest.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families.

Haplotype-tagging SNP analyses were conducted to identify molecular genetic substrates of quantitative phenotypes derived from performance on a Continuous Performance Task (CPT). Three hundred sixty-four individuals were sampled from 152 families ascertained on the basis of at least one child having ADHD. Probands, their affected and unaffected siblings, and parents were administered a CPT. Four different components of performance were analyzed and tested for association with SNPs from 10 candidate genes involved in monoaminergic function. After correcting for multiple comparisons and controlling for multiple individuals from the same family, significant associations were identified between commission errors and SNPs in the DRD2 gene (rs2075654, rs1079596), and between reaction time variability and a SNP in the NET gene (rs3785155). These findings suggest that commission errors and reaction time variability are excellent candidates as ADHD endophenotypes based on previously published criteria. Results also shed light on the molecular genetic basis of specific processes that may underlie the disorder.

Periconceptional folate intake and neural tube defects.

Approximately 50% of neural tube defects may be folate-preventable and perhaps even more in other countries where prevalence is high. The Public Health Service has issued the recommendation that all women of childbearing age in the United States who are capable of becoming pregnant should consume 400 micrograms of folic acid/day for the purpose of reducing this risk. Ways in which a reproductive age woman could achieve this goal include: 1) fortifying a food sample with folic acid, 2) consuming supplements containing at least 400 mcg of folic acid, or 3) increasing nutrient intake by eating foods rich in folate. Advantages of consuming foods high in folate content are that it is a natural behavior and consistent with other dietary recommendations. However, this method is dependent upon a proper diet, and equivalencies of conjugated (dietary form) vs. unconjugated (in supplements) folate are unknown. The benefit of a supplementation policy is that the appropriate group can be targeted as pregnancies are planned, whereas primary limitations to taking a supplement would be compliance and most cases in need would not be reached. The advantage of fortification is that it is likely to reach everyone before conception, while the major disadvantage is that nontargeted populations will also receive more folic acid. Adequate consumption of folic acid should begin before and continue during at least the first 4 weeks after conception when the fetal neural tube is being formed. Standard methods of screening for neural tube defects should continue during pregnancy. The risk of a recurrent neural tube defect is 2-3%, and a higher periconception daily intake of folic acid (4 mg per day) is recommended.

Bone-conduction electrocochleography: clinical applications.

Cases are presented which show the clinical utility of recording an electrocochleographic response to bone-conducted stimuli. The procedure is fraught with problems of acoustic control and artifact generation, but has distinct although limited values in clarifying masking dilemmas in patients with bilateral hearing loss.

Complications of percutaneous transtracheal procedures.

The increasing use of transtracheal procedures by various specialties has caused a rash of new complications which have interested the endoscopist. These complications have resulted from the many diagnostic and therapeutic procedures involving the percutaneous puncture of the laryngeal or tracheal air space. The validity of these procedures is not questioned. However, they have spawned a host of diverse and bizarre complications which have led to serious and even fatal problems. The role of the endoscopist as a consultant in both the diagnosis and therapy of these developments must be understood and stressed.