Latest Articles Include:
- Conclusion by exclusion
- Nature genetics 42(2):95 (2010)
Systems models and biomarker studies both pose the problem of wrangling high information content. Such publications can be made easier to review and to use if they propose explicit alternative hypotheses and show experimental exclusion of each competing explanation. In practice, we will need to be able to identify and independently cite multiple hypotheses and related experiments within a published work. - Inborn variation in metabolism
- Nature genetics 42(2):97-98 (2010)
Advances in analytical biochemistry have recently made it possible to obtain global snapshots of metabolism. A new study couples such technology with genome-wide genetic analysis to explore inherited variation in human metabolism. - Channelopathies converge on TRPV4
- Nature genetics 42(2):98-100 (2010)
Scapuloperoneal spinal muscular atrophy and Charcot-Marie-Tooth disease type 2C are inherited neurodegenerative diseases characterized by sensory defects and muscle weakness. Three new studies demonstrate that they are allelic disorders caused by mutations in the vanilloid transient receptor potential cation-channel gene TRPV4. - Deregulation of H3K27 methylation in cancer
- Nature genetics 42(2):100-101 (2010)
A new study now reports recurrent somatic mutation of EZH2, a histone methyltransferase that modifies H3K27, in diffuse large B-cell lymphoma (DLBCL). There is now evidence for both increased and decreased activity of enzymes controlling H3K27 methylation in cancer, suggesting that a precise balance of this methylation is critical for normal cell growth. - Research highlights
- Nature genetics 42(2):103 (2010)
- New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
- Nature genetics 42(2):105-116 (2010)
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results! demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. - Several common variants modulate heart rate, PR interval and QRS duration
- Nature genetics 42(2):117-122 (2010)
Electrocardiographic measures are indicative of the function of the cardiac conduction system. To search for sequence variants that modulate heart rate, PR interval and QRS duration in individuals of European descent, we performed a genome-wide association study in ~10,000 individuals and followed up the top signals in an additional ~10,000 individuals. We identified several genome-wide significant associations (with P < 1.6 × 10−7). We identified one locus for heart rate (MYH6), four for PR interval (TBX5, SCN10A, CAV1 and ARHGAP24) and four for QRS duration (TBX5, SCN10A, 6p21 and 10q21). We tested for association between these loci and subjects with selected arrhythmias in Icelandic and Norwegian case-control sample sets. We observed correlations between TBX5 and CAV1 and atrial fibrillation (P = 4.0 × 10−5 and P = 0.00032, respectively), between TBX5 and advanced atrioventricular block (P = 0.0067), and between SCN10A and pacemaker implantation (P = 0.0029). ! We also replicated previously described associations with the QT interval. - Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci
- Nature genetics 42(2):123-127 (2010)
To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the ! interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility. - Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1
- Nature genetics 42(2):128-131 (2010)
The major mood disorders, which include bipolar disorder and major depressive disorder (MDD), are considered heritable traits, although previous genetic association studies have had limited success in robustly identifying risk loci. We performed a meta-analysis of five case-control cohorts for major mood disorder, including over 13,600 individuals genotyped on high-density SNP arrays. We identified SNPs at 3p21.1 associated with major mood disorders (rs2251219, P = 3.63 × 10−8; odds ratio = 0.87; 95% confidence interval, 0.83–0.92), with supportive evidence for association observed in two out of three independent replication cohorts. These results provide an example of a shared genetic susceptibility locus for bipolar disorder and MDD. - Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk
- Nature genetics 42(2):132-136 (2010)
To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 × 10−9), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 × 10−10), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 × 10−7) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 × 10−7). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 × 10−6) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 × 10−6). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy. - A genome-wide perspective of genetic variation in human metabolism
Illig T Gieger C Zhai G Römisch-Margl W Wang-Sattler R Prehn C Altmaier E Kastenmüller G Kato BS Mewes HW Meitinger T de Angelis MH Kronenberg F Soranzo N Wichmann HE Spector TD Adamski J Suhre K - Nature genetics 42(2):137-141 (2010)
Serum metabolite concentrations provide a direct readout of biological processes in the human body, and they are associated with disorders such as cardiovascular and metabolic diseases. We present a genome-wide association study (GWAS) of 163 metabolic traits measured in human blood from 1,809 participants from the KORA population, with replication in 422 participants of the TwinsUK cohort. For eight out of nine replicated loci (FADS1, ELOVL2, ACADS, ACADM, ACADL, SPTLC3, ETFDH and SLC16A9), the genetic variant is located in or near genes encoding enzymes or solute carriers whose functions match the associating metabolic traits. In our study, the use of metabolite concentration ratios as proxies for enzymatic reaction rates reduced the variance and yielded robust statistical associations with P values ranging from 3 × 10−24 to 6.5 × 10−179. These loci explained 5.6%–36.3% of the observed variance in metabolite concentrations. For several loci, associations with! clinically relevant parameters have been reported previously. - Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge
- Nature genetics 42(2):142-148 (2010)
Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13! C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18). - Genetic variation in SCN10A influences cardiac conduction
- Nature genetics 42(2):149-152 (2010)
To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 × 10−15) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10−5 to 10−20). SCN10A encodes NaV1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a−/− mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricu! lar fibrillation. - Genome-wide association study of PR interval
- Nature genetics 42(2):153-159 (2010)
The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 × 10−8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental gen! es in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation. - Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C
Auer-Grumbach M Olschewski A Papić L Kremer H McEntagart ME Uhrig S Fischer C Fröhlich E Bálint Z Tang B Strohmaier H Lochmüller H Schlotter-Weigel B Senderek J Krebs A Dick KJ Petty R Longman C Anderson NE Padberg GW Schelhaas HJ van Ravenswaaij-Arts CM Pieber TR Crosby AH Guelly C - Nature genetics 42(2):160-164 (2010)
Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families. Expression of mutant TRPV4 constructs in cells from the HeLa line revealed diminished surface localization of mutant proteins. In addition, TRPV4-regulated Ca2+ influx was substantially reduced even after stimulation with 4αPDD, a TRPV4 channel-specific agonist, and with hypo-osmotic solution. In summary, we describe a new hereditary channelopathy caused by mutations in TRPV4 and present evidence that the resulting substitutions in the N-terminal ankyrin domain affect channel maturation! , leading to reduced surface expression of functional TRPV4 channels. - Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4
Deng HX Klein CJ Yan J Shi Y Wu Y Fecto F Yau HJ Yang Y Zhai H Siddique N Hedley-Whyte ET Delong R Martina M Dyck PJ Siddique T - Nature genetics 42(2):165-169 (2010)
Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy type IIC (HMSN IIC, also known as HMSN2C or Charcot-Marie-Tooth disease type 2C (CMT2C)) are phenotypically heterogeneous disorders involving topographically distinct nerves and muscles. We originally described a large New England family of French-Canadian origin with SPSMA and an American family of English and Scottish descent with CMT2C1, 2. We mapped SPSMA and CMT2C risk loci to 12q24.1–q24.31 with an overlapping region between the two diseases3, 4. Further analysis reduced the CMT2C risk locus to a 4-Mb region5. Here we report that SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4). Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins. Our findings link mutations in TRPV4 to altere! d calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism and possible options for therapy for these disorders. - Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C
Landouré G Zdebik AA Martinez TL Burnett BG Stanescu HC Inada H Shi Y Taye AA Kong L Munns CH Choo SS Phelps CB Paudel R Houlden H Ludlow CL Caterina MJ Gaudet R Kleta R Fischbeck KH Sumner CJ - Nature genetics 42(2):170-174 (2010)
Charcot-Marie-Tooth disease type 2C (CMT2C) is an autosomal dominant neuropathy characterized by limb, diaphragm and laryngeal muscle weakness. Two unrelated families with CMT2C showed significant linkage to chromosome 12q24.11. We sequenced all genes in this region and identified two heterozygous missense mutations in the TRPV4 gene, C805T and G806A, resulting in the amino acid substitutions R269C and R269H. TRPV4 is a well-known member of the TRP superfamily of cation channels. In TRPV4-transfected cells, the CMT2C mutations caused marked cellular toxicity and increased constitutive and activated channel currents. Mutations in TRPV4 were previously associated with skeletal dysplasias. Our findings indicate that TRPV4 mutations can also cause a degenerative disorder of the peripheral nerves. The CMT2C-associated mutations lie in a distinct region of the TRPV4 ankyrin repeats, suggesting that this phenotypic variability may be due to differential effects on regulatory ! protein-protein interactions. - AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis
- Nature genetics 42(2):175-180 (2010)
Degeneration of photoreceptors is a common feature of ciliopathies, owing to the importance of the specialized ciliary structure of these cells. Mutations in AHI1, which encodes a cilium-localized protein, have been shown to cause a form of Joubert syndrome that is highly penetrant for retinal degeneration1, 2. We show that Ahi1-null mice fail to form retinal outer segments and have abnormal distribution of opsin throughout their photoreceptors. Apoptotic cell death of photoreceptors occurs rapidly between 2 and 4 weeks of age in these mice and is significantly (P = 0.00175 and 0.00613) delayed by a reduced dosage of opsin. This phenotype also shows dosage-sensitive genetic interactions with Nphp1, another ciliopathy-related gene. Although it is not a primary cause of retinal blindness in humans, we show that an allele of AHI1 is associated with a more than sevenfold increase in relative risk of retinal degeneration within a cohort of individuals with the hereditary ki! dney disease nephronophthisis. Our data support context-specific roles for AHI1 as a contributor to retinopathy and show that AHI1 may explain a proportion of the variability in retinal phenotypes observed in nephronophthisis. - Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin
- Nature genetics 42(2):181-185 (2010)
Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells1. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-κB pathway2, 3 that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified4. Here we report recurrent somatic mutations affecting the polycomb-group oncogene5EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types6, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consiste! nt with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.
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