ABSTRACT
BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
Subject(s)
Chromosomes, Human, Pair 6/genetics , Osteoporosis/genetics , Osteoporotic Fractures/genetics , Case-Control Studies , Chromosome Breakpoints , Cohort Studies , DNA Copy Number Variations , DNA Mutational Analysis , Gene Deletion , Gene Dosage , Genome-Wide Association Study , Humans , Markov Chains , Middle AgedABSTRACT
Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (nâ=â1,397) and two Chinese Hong Kong sample sets (nâ=â3,869 and nâ=â785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, Pâ=â4.3×10(-9)), 1p31 (GPR177, Pâ=â0.00012), 3p22 (CTNNB1, Pâ=â0.00013), 4q22 (MEPE, Pâ=â0.0026), 5q14 (MEF2C, Pâ=â1.3×10(-5)), 6q25 (ESR1, Pâ=â0.0011), 7p14 (STARD3NL, Pâ=â0.00025), 7q21 (FLJ42280, Pâ=â0.00017), 8q24 (TNFRSF11B, Pâ=â3.4×10(-5)), 11p15 (SOX6, Pâ=â0.00033), 11q13 (LRP5, Pâ=â0.0033), 13q14 (TNFSF11, Pâ=â7.5×10(-5)), 16q24 (FOXL1, Pâ=â0.0010) and 17q21 (SOST, Pâ=â0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.
Subject(s)
Asian People/genetics , Bone Density/genetics , White People/genetics , Aged , Chromosome Mapping , Female , Genome-Wide Association Study , Hip , Humans , Male , Polymorphism, Single Nucleotide , SpineABSTRACT
Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
Subject(s)
Chromosomes, Human, Pair 4 , Genetic Predisposition to Disease , Genetic Variation , Urinary Bladder Neoplasms/genetics , Alleles , Disease-Free Survival , Europe , Female , Genotype , Humans , Male , Models, Genetic , Mutation , Receptor, Fibroblast Growth Factor, Type 3/genetics , Recurrence , Risk , SmokingABSTRACT
We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 x 10(-9), odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. Increased axon integrity observed in Lingo1 mouse [corrected] knockout models highlights the potential role of LINGO1 in the pathophysiology of ET [corrected]
Subject(s)
Essential Tremor/genetics , Genetic Predisposition to Disease , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Animals , Austria , Gene Frequency , Genetics, Population , Genome-Wide Association Study , Germany , Humans , Iceland , Linkage Disequilibrium , Mice , Mice, Knockout , Polymorphism, Single Nucleotide/physiology , Risk Factors , United StatesABSTRACT
OBJECTIVE: To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome-wide association study. METHODS: We genotyped 1,661 Icelandic IS patients and 10,815 control subjects using the Infinium HumanHap300 chip (Illumina, San Diego, CA). A total of 310,881 single nucleotide polymorphisms (SNPs) were tested for association with IS, and the most significant signals were replicated in two large European IS sample sets (2,224 cases/2,583 control subjects). Two SNPs, rs2200733 and rs10033464, were tested further in additional European IS samples (2,327 patients and 16,760 control subjects). RESULTS: In the Icelandic samples and the two replication sets combined, rs2200733 associated significantly with cardioembolic stroke (CES) (odds ratio [OR], 1.54; p = 8.05 x 10(-9)). No other variants associated with IS or any of its subtypes. rs2200733 associated significantly with IS in all sample sets combined (OR, 1.26; p = 2.18 x 10(-10)), and both rs2200733 and its neighbour, rs10033464 associated strongly with CES (rs2200733: OR, 1.52; p = 5.8 x 10(-12); rs10033464: OR, 1.27; p = 6.1 x 10(-4)). Interestingly, rs2200733 also showed significant association to IS not classified as CES. INTERPRETATION: We discovered that variants previously shown to associate with atrial fibrillation (AF), rs2200733 and rs10033464, significantly associated with IS, with the strongest risk for CES. The association with noncardiogenic stroke is intriguing and suggests that atrial fibrillation may be underdiagnosed in patients presenting with stroke. This discovery may have implications for workup and treatment of IS.
Subject(s)
Atrial Fibrillation/genetics , Chromosomes, Human, Pair 4 , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide/genetics , Stroke/genetics , Atrial Fibrillation/complications , Confidence Intervals , Female , Gene Frequency , Genotype , Humans , Male , Odds Ratio , Phenotype , Risk Factors , Stroke/etiology , White People/geneticsABSTRACT
The genome-wide recombination rate varies between individuals, but the mechanism controlling this variation in humans has remained elusive. A genome-wide search identified sequence variants in the 4p16.3 region correlated with recombination rate in both males and females. These variants are located in the RNF212 gene, a putative ortholog of the ZHP-3 gene that is essential for recombinations and chiasma formation in Caenorhabditis elegans. It is noteworthy that the haplotype formed by two single-nucleotide polymorphisms (SNPs) associated with the highest recombination rate in males is associated with a low recombination rate in females. Consequently, if the frequency of the haplotype changes, the average recombination rate will increase for one sex and decrease for the other, but the sex-averaged recombination rate of the population can stay relatively constant.
Subject(s)
Chromosomes, Human, Pair 4/genetics , Genome, Human , Recombination, Genetic , Ubiquitin-Protein Ligases/genetics , Alleles , Fathers , Female , Haplotypes , Humans , Ligases , Linkage Disequilibrium , Male , Meiosis , Molecular Sequence Data , Mothers , Polymorphism, Single Nucleotide , Sex Characteristics , Synaptonemal Complex/metabolismABSTRACT
BACKGROUND: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. METHODS: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. RESULTS: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). CONCLUSIONS: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.
Subject(s)
Nocturnal Myoclonus Syndrome/genetics , Restless Legs Syndrome/genetics , Transcription Factors/genetics , Case-Control Studies , Chromosomes, Human, Pair 6 , Female , Ferritins/blood , Genetic Markers , Genetic Predisposition to Disease , Genome, Human , Genotype , Humans , Iron Deficiencies , Linkage Disequilibrium , Male , Nerve Tissue Proteins , Nocturnal Myoclonus Syndrome/blood , Polymorphism, Single Nucleotide , Restless Legs Syndrome/blood , Risk FactorsABSTRACT
The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.
Subject(s)
Chromosomes, Human, Pair 9/genetics , Genetic Predisposition to Disease , Genetic Variation , Myocardial Infarction/genetics , Polymorphism, Single Nucleotide , Age of Onset , Aged , Case-Control Studies , Chromosome Mapping , Coronary Artery Disease/genetics , Female , Genes, p16 , Genotype , Haplotypes , Heterozygote , Homozygote , Humans , Linkage Disequilibrium , Male , Middle Aged , Risk FactorsABSTRACT
Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.
