GRR: graphical representation of relationship errors
ABSTRACT A graphical tool for verifying assumed relationships between individuals in genetic studies is described. GRR can detect many common errors using genotypes from many markers. AVAILABILITY: GRR is available at http://bioinformatics.well.ox.ac.uk/GRR.
Full-textDOI: · Available from: Stacey Cherny, Jul 29, 2015
- SourceAvailable from: Joseph H Lee
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- "The genotype data included ∼2.3 million SNPs from the Illumina Omni chip. Quality control was performed before imputation by checking pedigree relationships using GRR (Abecasis et al., 2001) and Loki (Heath, 1997) approaches. Single-nucleotide polymorphism (SNPs) were eliminated if presented Mendelian errors, coded allele frequency <1% or >99%, deviations from Hardy-Weinberg equilibrium (p < 1.0 × 10 −6 ), and/or low call rate (98%). "
ABSTRACT: The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.Frontiers in Genetics 06/2014; 5:159. DOI:10.3389/fgene.2014.00159
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- "The gender of samples was verified by counting heterozygous single nucleotide polymorphisms on the X chromosome. Relationship errors were evaluated with the help of the program Graphical Representation of Relationships (GRR) (Abecasis et al., 2001). For log of odds (LOD) score calculations, we assumed six consanguineous families with one child from second cousin marriages, an approach useful for identification of rare recessive disorders when consanguinity was not proven a priori (Rutsch et al., 2009). "
ABSTRACT: A cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy was previously reported in three Dutch families. Here we report the genetic cause of this disorder. Multipoint parametric linkage analysis of six Dutch patients identified a homozygous region of 2.1 Mb on chromosome 12, which was shared between all Dutch patients, with a log of odds score of 10.82. Sequence analysis of the entire linkage region resulted in the identification of a homozygous mutation in the last acceptor splice site of the myosin regulatory light chain 2 gene (MYL2) as the genetic cause. MYL2 encodes a myosin regulatory light chain (MLC-2V). The myosin regulatory light chains bind, together with the essential light chains, to the flexible neck region of the myosin heavy chain in the hexameric myosin complex and have a structural and regulatory role in muscle contraction. The MYL2 mutation results in use of a cryptic splice site upstream of the last exon causing a frameshift and replacement of the last 32 codons by 20 different codons. Whole exome sequencing of an Italian patient with similar clinical features showed compound heterozygosity for two other mutations affecting the same exon of MYL2, also resulting in mutant proteins with altered C-terminal tails. As a consequence of these mutations, the second EF-hand domain is disrupted. EF-hands, assumed to function as calcium sensors, can undergo a conformational change upon binding of calcium that is critical for interactions with downstream targets. Immunohistochemical staining of skeletal muscle tissue of the Dutch patients showed a diffuse and weak expression of the mutant protein without clear fibre specificity, while normal protein was absent. Heterozygous missense mutations in MYL2 are known to cause dominant hypertrophic cardiomyopathy; however, none of the parents showed signs of cardiomyopathy. In conclusion, the mutations in the last exon of MYL2 are responsible for a novel autosomal recessive lethal myosinopathy due to defects changing the C-terminal tail of the ventricular form of the myosin regulatory light chain. We propose 'light chain myopathy' as a name for this MYL2-associated myopathy.Brain 01/2013; 136(Pt 1):282-93. DOI:10.1093/brain/aws293 · 10.23 Impact Factor
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- "University in Saint Louis. QC was performed before imputation and included assessment of Mendelian errors as implemented in LOKI (Heath, 1997) and verification of reported pedigree relationships using GRR (Abecasis et al., 2001). "
ABSTRACT: Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes-TERC, MYNN, and OBFC1-were significantly associated with leukocyte telomere length at p empirical < 0.05.Frontiers in Genetics 01/2013; 4:310. DOI:10.3389/fgene.2013.00310