Genetic association analyses of nitric oxide synthase genes and neural tube defects vary by phenotype.

Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed.

Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy.

Excitation-contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca(2+) from internal stores to initiate muscle contraction. Defects in excitation-contraction coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the excitation-contraction coupling machinery.

Folate metabolism genes, dietary folate and response to antidepressant medications in late-life depression.

Objective: The primary aims of this study were to (i) determine whether folate metabolism genetic polymorphisms predict age of onset and occurrence of late life depression; and (ii) determine whether folate metabolism genetic polymorphisms predict response to antidepressant medications in late-life depression.

Methods: This study used the Conte Center for the Neuroscience of Depression and the Neurocognitive Outcomes of Depression in the Elderly Study database, which includes individuals aged ≥60. The folate nutrition assessment was determined by the Block Food Frequency Questionnaire.

Transcriptome profiling of genes involved in neural tube closure during human embryonic development using long serial analysis of gene expression (long-SAGE).

Background: Neural tube defects (NTDs) are common human birth defects with a complex etiology. To develop a comprehensive knowledge of the genes expressed during normal neurulation, we established transcriptomes from human neural tube fragments during and after neurulation using long Serial Analysis of Gene Expression (long-SAGE).

Methods: Rostral and caudal neural tubes were dissected from normal human embryos aged between 26 and 32 days of gestation.

Clinical, radiological, and genetic similarities between patients with Chiari Type I and Type 0 malformations.

Object: Although Chiari Type I (CM-I) and Type 0 (CM-0) malformations have been previously characterized clinically and radiologically, there have been no studies focusing on the possible genetic link between these disorders. The goal of this study was to identify families in whom CM-0 and CM-I co-occurred and to further assess the similarities between these disorders.

Methods: Families were ascertained through a proband with CM-I.

A common MUC5B promoter polymorphism and pulmonary fibrosis.

Background: The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk.

Methods: Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families.

Natural food folate and late-life depression.

Low folate status has been linked to depression, but findings have been inconsistent. The authors sought to examine the association between folate intake and late-life depression. This cross-sectional study included individuals age 60 and older (n = 111 depression, n = 136 comparison).

Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects.

Background: Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors.

Methods: We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families.

Human neural crest cells display molecular and phenotypic hallmarks of stem cells.

The fields of both developmental and stem cell biology explore how functionally distinct cell types arise from a self-renewing founder population. Multipotent, proliferative human neural crest cells (hNCC) develop toward the end of the first month of pregnancy. It is assumed that most differentiate after migrating throughout the organism, although in animal models neural crest stem cells reportedly persist in postnatal tissues.

Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia.

Native American myopathy (NAM) [OMIM 255995], a putative autosomal recessive disorder, was first reported in the Lumbee Indians of North Carolina. NAM features include congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH) provoked by anesthesia. This report documents the phenotypic complexity and natural history of this rare congenital disorder in fourteen individuals with NAM.

Refinement of 2q and 7p loci in a large multiplex NTD family.

Background: NTDs are considered complex disorders that arise from an interaction between genetic and environmental factors. NTD family 8776 is a large multigenerational Caucasian family that provides a unique resource for the genetic analysis of NTDs. Previous linkage analysis using a genome-wide SNP screen in family 8776 with multipoint nonparametric mapping methods identified maximum LOD* scores of approximately 3.

Use of LINKAGE programs for linkage analysis.

Genetic linkage analysis remains a powerful tool for identifying regions of the genome that may harbor suceptibility loci. This unit describes the traditional approach of calculating two-point and multipoint lod scores when the underlying genetic model is known. Components of the genetic model include whether a trait is dominant, recessive, or codominant, whether it is autosomal or sex linked, and whether there is mutation at the disease gene locus, as well as the disease and marker allele frequencies and the penetrance of the disease allele.

The brain-derived neurotrophic factor VAL66MET polymorphism and cerebral white matter hyperintensities in late-life depression.

Objective: In animal models, brain-derived neurotrophic factor (BDNF) appears to protect against cerebral ischemia. The authors examined whether the BDNF Val66Met polymorphism, which affects BDNF distribution, was associated with greater volumes of hyperintense lesions as detected on magnetic resonance imaging in a cohort of depressed and nondepressed elders.

Design: Subjects completed cross-sectional assessments, including clinical evaluation and a brain magnetic resonance imaging scan, and provided blood samples for Val66Met genotyping.

Estimated fumonisin exposure in Guatemala is greatest in consumers of lowland maize.

Fumonisin mycotoxins contaminate maize worldwide. Analysis of maize samples (n = 396) collected from fields in Guatemala from 2000 to 2003 found that lowland maize (<360 m) had significantly more fumonisin B1 than highland maize (>1200 m). For example, 78% of the lowland samples collected at harvest in 2002 contained >0.

Allelic differences in the brain-derived neurotrophic factor Val66Met polymorphism in late-life depression.

Objective: The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with cognitive and neuroimaging changes. The authors examined the relationship between this polymorphism and depression in an elderly sample, hypothesizing that the Met66 allele would be associated with late-life depression.

Methods: A total of 245 elderly depressed white subjects and 94 elderly comparison white subjects completed clinical assessments and provided a blood sample for genotyping.

Association of AGTR1 with 18-month treatment outcome in late-life depression.

Objective: Converging lines of evidence implicate vascular factors in late-life depression, and argue that late-life depression is a distinct entity among the mood disorders. The A1166C polymorphism in the angiotensin II receptor, vascular type 1 (AGTR1) gene has been associated with a range of vascular diseases. This study investigated the association of AGTR1 genotype on 18-month treatment outcome in late-life depression.

Update on psychiatric genetics.

Genetic factors play a fundamental role in the genesis of many mental disorders. The identification of the underlying genetic variation will therefore transform parts of psychiatry toward a neuroscience-based discipline. With the sequence of the human genome now available, the majority of common variations identified, and new high-throughput technologies arriving in academic research laboratories, the identification of genes is expected to explain a large proportion of the risk of developing mental disorders.

Phenotypic definition of Chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15.

Chiari type I malformation (CMI; OMIM 118420) is narrowly defined when the tonsils of the cerebellum extend below the foramen magnum, leading to a variety of neurological symptoms. It is widely thought that a small posterior fossa (PF) volume, relative to the total cranial volume leads to a cramped cerebellum and herniation of the tonsils into the top of the spinal column. In a collection of magnetic resonance imagings (MRIs) from affected individuals and their family members, we measured correlations between ten cranial morphologies and estimated their heritability in these families.

Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions.

Background: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results.

Objectives: Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation.

Gene expression profiling of familial and sporadic interstitial pneumonia.

Rationale: Idiopathic interstitial pneumonia (IIP) and its familial variants are progressive and largely untreatable disorders with poorly understood molecular mechanisms. Both the genetics and the histologic type of IIP play a role in the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown.

Objectives: To evaluate gene expression in the lung tissue of patients with usual interstitial pneumonia or nonspecific interstitial pneumonia that was either familial or nonfamilial in origin, and to compare it with gene expression in normal lung parenchyma.

High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35.

Background: Neural tube defects (NTDs) are considered complex, with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs demonstrated evidence of linkage to chromosomes 7 and 10.

Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2.

Background: Vitamin A (retinol), in the form of retinoic acid (RA), is essential for normal development of the human embryo. Studies in the mouse and zebrafish have shown that retinol is metabolized in the developing spinal cord and must be maintained in a precise balance along the anteroposterior axis. Both excess and deficiency of RA can affect morphogenesis, including failures of neural tube closure.

Clinical and pathologic features of familial interstitial pneumonia.

Rationale: Several lines of evidence suggest that genetic factors and environmental exposures play a role in the development of pulmonary fibrosis.

Objectives: We evaluated families with 2 or more cases of idiopathic interstitial pneumonia among first-degree family members (familial interstitial pneumonia, or FIP), and identified 111 families with FIP having 309 affected and 360 unaffected individuals.

Methods: The presence of probable or definite FIP was based on medical record review in 28 cases (9.

Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing.

Objectives: Describe the inflation in nonparametric multipoint LOD scores due to inter-marker linkage disequilibrium (LD) across many markers with varied allele frequencies.

Method: Using simulated two-generation families with and without parents, we conducted nonparametric multipoint linkage analysis with 2 to 10 markers with minor allele frequencies (MAF) of 0.5 and 0.