Latest Articles Include:
- The cup half empty
- Nat Genet 41(6):635 (2009)
One-sixth of the world's population does not have enough food to sustain life, and the world's food supply needs to double by 2050 without increasing demand for water or fuel. Agricultural genetics is one of the easier parts of the solution. - Genetics of reproductive lifespan
- Nat Genet 41(6):637-638 (2009)
Five genome-wide association studies of the timing of menarche and menopause have now taken us beyond the range of candidate gene and linkage studies. The list of new genetic associations identified for these two traits should shed light on the mechanisms of ovarian aging, as well as breast cancer and other diseases associated with reproductive lifespan. - Diversifying microtubules in brain development
- Nat Genet 41(6):638-640 (2009)
Tubulins are key structural components of all cells. A new study reveals roles in brain development for a specific beta-tubulin isoform and highlights potential for functional diversity in the beta-tubulin gene family. - Narcolepsy and the T-cell receptor
- Nat Genet 41(6):640-641 (2009)
The etiology of the sleep disorder narcolepsy has not been firmly established, although an autoimmune pathogenesis has been proposed and is supported by a strong genetic association with the HLA. A new genome-wide association study provides further support for the autoimmune basis of narcolepsy by uncovering a robust association at the T-cell receptor alpha locus. - Research highlights
- Nat Genet 41(6):642 (2009)
I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Genetics Select this option to purchase a personal subscription to Nature Genetics. - Loci at chromosomes 13, 19 and 20 influence age at natural menopause
- Nat Genet 41(6):645-647 (2009)
We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; –0.4 year per T allele (39%); P = 6.3 times 10-11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 times 10-11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 times 10-8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease. - Meta-analysis of genome-wide association data identifies two loci influencing age at menarche
- Nat Genet 41(6):648-650 (2009)
We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 times 10-9), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 times 10-9), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation. - Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia
- Nat Genet 41(6):651-653 (2009)
The sideroblastic anemias are a heterogeneous group of congenital and acquired hematological disorders whose morphological hallmark is the presence of ringed sideroblasts—bone marrow erythroid precursors containing pathologic iron deposits within mitochondria. Here, by positional cloning, we define a previously unknown form of autosomal recessive nonsyndromic congenital sideroblastic anemia, associated with mutations in the gene encoding the erythroid specific mitochondrial carrier family protein SLC25A38, and demonstrate that SLC25A38 is important for the biosynthesis of heme in eukaryotes. - SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy
- Nat Genet 41(6):654-656 (2009)
We report mutations in SDHAF1, encoding a new LYR-motif protein, in infantile leukoencephalopathy with defective succinate dehydrogenase (SDH, complex II). Disruption of the yeast homolog or expression of variants corresponding to human mutants caused SDH deficiency and failure of OXPHOS-dependent growth, whereas SDH activity and amount were restored in mutant fibroblasts proportionally with re-expression of the wild-type gene. SDHAF1 is the first bona fide SDH assembly factor reported in any organism. - Genome-wide and fine-resolution association analysis of malaria in West Africa
- Nat Genet 41(6):657-665 (2009)
We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 times 10-7 to P = 4 times 10-14, with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing! data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations. - Genome-wide association study identifies eight loci associated with blood pressure
- Nat Genet 41(6):666-676 (2009)
Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N less than or equal to 71,225 European ancestry, N less than or equal to 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 times 10-24), CYP1A2 (P = 1 times 10-23), FGF5 (P = 1 times 10-21), SH2B3 (P = 3 times 10-18), MTHFR (P = 2 times 10-13), c10orf107 (P = 1 times 10-9), ZNF652 (P = 5 times 10-9) and PLCD3 (P = 1 times 10-8) genes. All variants associated with continuous blood pressur! e were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease. - Genome-wide association study of blood pressure and hypertension
- Nat Genet 41(6):677-687 (2009)
Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 times 10-7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 times 10-8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure a! dvances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension. - Usp46 is a quantitative trait gene regulating mouse immobile behavior in the tail suspension and forced swimming tests
- Nat Genet 41(6):688-695 (2009)
The tail suspension test (TST) and forced swimming test (FST) are widely used for assessing antidepressant activity and depression-like behavior. We found that CS mice show negligible immobility in inescapable situations. Quantitative trait locus (QTL) mapping using CS and C57BL/6J mice revealed significant QTLs on chromosomes 4 (FST) and 5 (TST and FST). To identify the quantitative trait gene on chromosome 5, we narrowed the QTL interval to 0.5 Mb using several congenic and subcongenic strains. Ubiquitin-specific peptidase 46 (Usp46) with a lysine codon deletion was located in this region. This deletion affected nest building, muscimol-induced righting reflex and anti-immobility effects of imipramine. The muscimol-induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase were significantly decreased in the Usp46 mutant mice compared to control mice. These phenotypes were rescued in transge! nic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects the immobility in the TST and FST, and it is implicated in the regulation of GABA action. - Retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine-5 methyltransferase DNMT2
- Nat Genet 41(6):696-702 (2009)
Here we show that the cytosine-5 methyltransferase DNMT2 controls retrotransposon silencing in Drosophila somatic cells. In Drosophila, significant DNMT2-dependent DNA methylation occurs during early embryogenesis. Suppression of white gene silencing by Mt2 (Dnmt2) null mutations in variegated P[w+] element insertions identified functional targets of DNMT2. The enzyme controls DNA methylation at retrotransposons in early embryos and initiates histone H4K20 trimethylation catalyzed by the SUV4-20 methyltransferase. In somatic cells, loss of DNMT2 eliminates H4K20 trimethylation at retrotransposons and impairs maintenance of retrotransposon silencing. In Dnmt2 and Suv4-20 null genotypes, retrotransposons are strongly overexpressed in somatic but not germline cells, where retrotransposon silencing depends on an RNAi mechanism. DNMT2 also controls integrity of chromosome 2R and 3R telomeres. In Dnmt2 null strains, we found stable loss of the subtelomeric clusters of defect! ive Invader4 elements. Together, these results demonstrate a previously unappreciated role of DNA methylation in retrotransposon silencing and telomere integrity in Drosophila. - Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes
- Nat Genet 41(6):703-707 (2009)
Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P < 10-6). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 times 10-8) and 4 additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27. - Narcolepsy is strongly associated with the T-cell receptor alpha locus
- Nat Genet 41(6):708-711 (2009)
Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals1, 2. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs5 and mice6, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported7, 8. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10-21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders! 9; thus, narcolepsy will provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders9. - Multiple loci associated with indices of renal function and chronic kidney disease
- Nat Genet 41(6):712-717 (2009)
Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity1. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m2) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 times 10-8) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein2, and rare mutations in UMOD cause mendelian forms of kidney disease3. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic! variants influencing renal function and disease. - Common variations in BARD1 influence susceptibility to high-risk neuroblastoma
- Nat Genet 41(6):718-723 (2009)
We conducted a SNP-based genome-wide association study (GWAS) focused on the high-risk subset of neuroblastoma1. As our previous unbiased GWAS showed strong association of common 6p22 SNP alleles with aggressive neuroblastoma2, we restricted our analysis here to 397 high-risk cases compared to 2,043 controls. We detected new significant association of six SNPs at 2q35 within the BARD1 locus (Pallelic = 2.35 times 10-9–2.25 times 10-8). We confirmed each SNP association in a second series of 189 high-risk cases and 1,178 controls (Pallelic = 7.90 times 10-7–2.77 times 10-4). We also tested the two most significant SNPs (rs6435862, rs3768716) in two additional independent high-risk neuroblastoma case series, yielding combined allelic odds ratios of 1.68 each (P = 8.65 times 10-18 and 2.74 times 10-16, respectively). We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of ! the aggressive and most clinically relevant subset of human neuroblastoma. - Genome-wide association studies identify loci associated with age at menarche and age at natural menopause
- Nat Genet 41(6):724-728 (2009)
Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 times 10-7–3 times 10-13) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 times 10-7–1 times 10-21) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits. - Genetic variation in LIN28B is associated with the timing of puberty
- Nat Genet 41(6):729-733 (2009)
The timing of puberty is highly variable1. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 times 10-8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08–0.16; P = 2.8 times 10-10; combined P = 3.6 times 10-16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 times 10-7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA pro! cessing2, as the first genetic determinant regulating the timing of human pubertal growth and development. - Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche
- Nat Genet 41(6):734-738 (2009)
Earlier menarche correlates with shorter adult height1 and higher childhood body fat2. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 times 10-14). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height3, 4. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height3, 4, 5, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass i! ndex (BMI)6, 7, 8, 9, 10, 11 and 5 of those associated with earlier AAM. - A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies
- Nat Genet 41(6):739-745 (2009)
Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromis! es this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect. - Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria
- Nat Genet 41(6):746-752 (2009)
Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissen! cephaly and pachygyria, but also polymicrogyria malformations. - Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates
Mátés L Chuah MK Belay E Jerchow B Manoj N Acosta-Sanchez A Grzela DP Schmitt A Becker K Matrai J Ma L Samara-Kuko E Gysemans C Pryputniewicz D Miskey C Fletcher B Vandendriessche T Ivics Z Izsvák Z - Nat Genet 41(6):753-761 (2009)
The Sleeping Beauty (SB) transposon is a promising technology platform for gene transfer in vertebrates; however, its efficiency of gene insertion can be a bottleneck in primary cell types. A large-scale genetic screen in mammalian cells yielded a hyperactive transposase (SB100X) with approx100-fold enhancement in efficiency when compared to the first-generation transposase. SB100X supported 35–50% stable gene transfer in human CD34+ cells enriched in hematopoietic stem or progenitor cells. Transplantation of gene-marked CD34+ cells in immunodeficient mice resulted in long-term engraftment and hematopoietic reconstitution. In addition, SB100X supported sustained (>1 year) expression of physiological levels of factor IX upon transposition in the mouse liver in vivo. Finally, SB100X reproducibly resulted in 45% stable transgenesis frequencies by pronuclear microinjection into mouse zygotes. The newly developed transposase yields unprecedented stable gene transfer effic! iencies following nonviral gene delivery that compare favorably to stable transduction efficiencies with integrating viral vectors and is expected to facilitate widespread applications in functional genomics and gene therapy. - Corrigendum: Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study
- Nat Genet 41(6):762 (2009)
Introduction Nat. Genet. 41, 216–220 (2009), published online 4 January 2009; corrected after print 28 April 2009 ADVERTISEMENT Advertisement In the first paragraph of the second column on the third page, rs11209026 A allele was incorrectly listed as rs111209026 A allele. The error has been corrected in the HTML and PDF versions of the article. - Corrigendum: Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis
- Nat Genet 41(6):762 (2009)
Introduction Nat. Genet. 41, 228–233 (2009), published online 4 January 2009; corrected after print 28 April 2009 ADVERTISEMENT Advertisement The affiliation of the 24th author, Alessandro Terrinoni, was listed incorrectly. It should read IDI-IRCCS Biochemistry Laboratory c/o Univ. Tor Vergata, 00133 Rome, Italy. The error has been corrected in the HTML and PDF versions of this article. - Corrigendum: Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants
- Nat Genet 41(6):762 (2009)
Introduction Nat. Genet. 41, 334–341 (2009); published online 8 February 2009; corrected after print 27 May 2009 ADVERTISEMENT Advertisement In the version of this article initially published, the names of four co-authors (Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent Mooser) were omitted from the author list. The error has been corrected in the HTML and PDF versions of the article. - Addendum: Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing
- Nat Genet 41(6):762 (2009)
Introduction Nat. Genet. 40, 1413–1415 (2008), published online 2 November 2008; addendum published after print 28 April 2009 The GEO accession number for the mRNA-Seq datasets is GSE13652.
No comments:
Post a Comment