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Exome Analysis of Two Limb-Girdle Muscular Dystrophy Families: Mutations Identified and Challenges Encountered

The molecular diagnosis of muscle disorders is challenging: genetic heterogeneity (>100 causal genes for skeletal and cardiac muscle disease) precludes exhaustive clinical testing, prioritizing sequencing of specific genes is difficult due to the similarity of clinical presentation, and the number of variants returned through exome sequencing can make the identification of the...

An Examination of the Association between 5-HTTLPR, Combat Exposure, and PTSD Diagnosis among U.S. Veterans

Objective To examine the association between the 5-HTTLPR polymorphism of the serotonin transporter (SLC6A4) gene, combat exposure, and posttraumatic stress disorder (PTSD) diagnosis and among two samples of combat-exposed veterans. Method The first sample included 550 non-Hispanic Black (NHB) combat-exposed veterans. The second sample included 555 non-Hispanic White (NHW) combat...

Spink2 Modulates Apoptotic Susceptibility and Is a Candidate Gene in the Rgcs1 QTL That Affects Retinal Ganglion Cell Death after Optic Nerve Damage

The Rgcs1 quantitative trait locus, on mouse chromosome 5, influences susceptibility of retinal ganglion cells to acute damage of the optic nerve. Normally resistant mice (DBA/2J) congenic for the susceptible allele from BALB/cByJ mice exhibit susceptibility to ganglion cells, not only in acute optic nerve crush, but also to chronic inherited glaucoma that is characteristic of...

Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10−11). SIX6 plays a role in ocular development and...

Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder

Background Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD). Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4) have been...

Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations

We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter ‘523’, based on the number of ‘T’-residues: ‘Short’ (S, T≤19), ‘Long’ (L, 20≤T≤29) and ‘Very Long...

Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling

Sarcomeric α-actinins (α-actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific α-actinin-3 in ∼20% of the general population. α-Actinin-3 deficiency is...

Genome-Wide Linkage Scan for Primary Open Angle Glaucoma: Influences of Ancestry and Age at Diagnosis

Primary open-angle glaucoma (POAG) is the most common form of glaucoma and one of the leading causes of vision loss worldwide. The genetic etiology of POAG is complex and poorly understood. The purpose of this work is to identify genomic regions of interest linked to POAG. This study is the largest genetic linkage study of POAG performed to date: genomic DNA samples from 786...

Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM

Myotilin is a muscle-specific Z-disc protein with putative roles in myofibril assembly and structural upkeep of the sarcomere. Several myotilin point mutations have been described in patients with limb-girdle muscular dystrophy type 1A (LGMD1A), myofibrillar myopathy (MFM), spheroid body myopathy (SBM), three similar adult-onset, progressive and autosomal dominant muscular...

Replication of TCF4 through Association and Linkage Studies in Late-Onset Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18...

A High-Density Genome-Wide Association Screen of Sporadic ALS in US Veterans

Following reports of an increased incidence of amyotrophic lateral sclerosis (ALS) in U.S. veterans, we have conducted a high-density genome-wide association study (GWAS) of ALS outcome and survival time in a sample of U.S. veterans. We tested ∼1.3 million single nucleotide polymorphisms (SNPs) for association with ALS outcome in 442 incident Caucasian veteran cases diagnosed...

Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration

Age-related macular degeneration (AMD) impairs vision for ∼7.5 million Americans. Both susceptibility variants and protective haplotypes in the complement factor H (CFH) gene modulate risk for AMD. Recently, deletion of the ‘CFH-related’ genes CFHR1 and CFHR3 was found to be segregating with a particular CFH haplotype, which reduced the risk of AMD. We tested the deletion for...

GALC Deletions Increase the Risk of Primary Open-Angle Glaucoma: The Role of Mendelian Variants in Complex Disease

DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the...

Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration

Age-related macular degeneration (AMD) is a devastating disorder of the central retina, causing significant visual impairment for 7.5 million elderly Americans. Abnormal regulation of the complement system likely caused by the Y402H polymorphism in the complement factor H gene is a recognized risk factor for AMD, as is the A69S variant in the poorly characterized LOC387715 gene...

Mitochondrial DNA Polymorphism A4917G Is Independently Associated with Age-Related Macular Degeneration

The objective of this study was to determine if MTND2*LHON4917G (4917G), a specific non-synonymous polymorphism in the mitochondrial genome previously associated with neurodegenerative phenotypes, is associated with increased risk for age-related macular degeneration (AMD). A preliminary study of 393 individuals (293 cases and 100 controls) ascertained at Vanderbilt revealed an...

A common variant near TGFBR3 is associated with primary open angle glaucoma

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from...

SNPselector: a web tool for selecting SNPs for genetic association studies

Summary: Single nucleotide polymorphisms (SNPs) are commonly used for association studies to find genes responsible for complex genetic diseases. With the recent advance of SNP technology, researchers are able to assay thousands of SNPs in a single experiment. But the process of manually choosing thousands of genotyping SNPs for tens or hundreds of genes is time consuming. We...

ABCC5, a Gene That Influences the Anterior Chamber Depth, Is Associated with Primary Angle Closure Glaucoma

Allingham Michael A. Hauser Nagaswamy Soumittra Vedam L. Ramprasad Naushin Waseem Azhany Yaakub Kee-Seng Chia Govindasamy Kumaramanickavel Tina T. Wong Alicia C. How Tran Nguyen Bich Chau Cameron P. Simmons

Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure...

Genomic convergence: identifying candidate genes for Parkinson's disease by combining serial analysis of gene expression and genetic linkage

We present a multifactorial, multistep approach called genomic convergence that combines gene expression with genomic linkage analysis to identify and prioritize candidate susceptibility genes for Parkinson's disease (PD). To initiate this process, we used serial analysis of gene expression (SAGE) to identify genes expressed in two normal substantia nigras (SN) and adjacent...