Alzheimer disease (AD) is a huge and growing societal problem with upwards of 35% of the population over the age of 80 developing the disease. AD results in a loss of memory, the ability to make ...reasoned and sound decisions, and ultimately the inability to take care of oneself. AD has an impact not only on the sufferer, but their caretakers and loved ones, who must take on a costly and time-consuming burden of care. AD is found in virtually all racial and ethnic groups. Genetic influences on AD are substantial, and there has been a 30 year history of both success and failure. Mutations for rare early onset forms of the disease have been identified, but this information has not yet led to an effective treatment. Multiple common genetic variations have also been identified, and have led to new insights into the potential role of microglia cells in addition to neuronal cells in the brain. Despite intensive efforts, a significant portion of the genetic etiology of AD remains unknown and must be identified.
Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. ...Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in two additional individuals. These recurrent mutations all occur within or in very close proximity to sites that regulate mtDNA replication, strongly implying that these variations alter the replication dynamics of the mutated mtDNA genome. These recurrent variants are all independent of each other and do not occur in the mtDNA coding regions. The most parsimonious explanation of the data is that these frequently repeated mutations experience tissue-specific positive selection, probably through replication advantage.
Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by motor-neuron degeneration in the brain and spinal cord. Most cases of ALS are sporadic but about 5-10% are ...familial. Mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP, also known as TDP43) and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS)) account for approximately 30% of classic familial ALS. Mutations in several other genes have also been reported as rare causes of ALS or ALS-like syndromes. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin 2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin 2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.
The Electronic Medical Records and Genomics Network is a National Human Genome Research Institute–funded consortium engaged in the development of methods and best practices for using the electronic ...medical record as a tool for genomic research. Now in its sixth year and second funding cycle, and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from electronic medical records can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and health-care informatics, particularly for electronic phenotyping, genome-wide association studies, genomic medicine implementation, and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here, we describe the evolution, accomplishments, opportunities, and challenges of the network from its inception as a five-group consortium focused on genotype–phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting toward the implementation of genomic medicine.
Genet Med15 10, 761–771.
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. ...Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Improving accuracy in genetic studies would greatly accelerate understanding the genetic basis of complex diseases. One approach to achieve such an improvement for risk variants identified by the ...genome wide association study (GWAS) approach is to incorporate previously known biology when screening variants across the genome. We developed a simple approach for improving the prioritization of candidate disease genes that incorporates a network diffusion of scores from known disease genes using a protein network and a novel integration with GWAS risk scores, and tested this approach on a large Alzheimer disease (AD) GWAS dataset. Using a statistical bootstrap approach, we cross-validated the method and for the first time showed that a network approach improves the expected replication rates in GWAS studies. Several novel AD genes were predicted including CR2, SHARPIN, and PTPN2. Our re-prioritized results are enriched for established known AD-associated biological pathways including inflammation, immune response, and metabolism, whereas standard non-prioritized results were not. Our findings support a strategy of considering network information when investigating genetic risk factors.
Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in the elderly whose etiology remains largely unknown. Previous studies identified chromosome 1q32 as ...harboring a susceptibility locus for AMD. We used single-nucleotide polymorphisms to interrogate this region and identified a strongly associated haplotype in two independent data sets. DNA resequencing of the complement factor H gene within this haplotype revealed a common coding variant, Y402H, that significantly increases the risk for AMD with odds ratios between 2.45 and 5.57. This common variant likely explains approximately43% of AMD in older adults.
We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an ...independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.
We carried out a genome-wide association study among Chinese women to identify risk variants for breast cancer. After analyzing 607,728 SNPs in 1,505 cases and 1,522 controls, we selected 29 SNPs for ...a fast-track replication in an independent set of 1,554 cases and 1,576 controls. We further investigated four replicated loci in a third set of samples comprising 3,472 cases and 900 controls. SNP rs2046210 at 6q25.1, located upstream of the gene encoding estrogen receptor α (ESR1), showed strong and consistent association with breast cancer across all three stages. Adjusted odds ratio (95% CI) were 1.36 (1.24-1.49) and 1.59 (1.40-1.82), respectively, for genotypes A/G and A/A versus G/G (P for trend 2.0 × 10−15) in the pooled analysis of samples from all three stages. We also found a similar, albeit weaker, association in an independent study comprising 1,591 cases and 1,466 controls of European ancestry (Ptrend = 0.01). These results strongly implicate 6q25.1 as a susceptibility locus for breast cancer.
Glaucoma is the leading cause of irreversible blindness globally
. Despite its gravity, the disease is frequently undiagnosed in the community
. Raised intraocular pressure (IOP) is the most ...important risk factor for primary open-angle glaucoma (POAG)
. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.
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