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author:("Liu, chungju")
1.  A rare mutation of CACNA1C in a patient with Bipolar disorder, and decreased gene expression associated with a Bipolar-associated common SNP of CACNA1C in brain 
Molecular psychiatry  2013;19(8):890-894.
Timothy Syndrome (TS) is caused by very rare exonic mutations of the CACNA1C gene that produce delayed inactivation of Cav1.2voltage-gated calcium channels during cellular action potentials, with greatly increased influx of calcium into the activated cells. The major clinical feature of this syndrome is a long QT interval that results in cardiac arrhythmias. However, TS also includes cognitive impairment, autism, and major developmental delays in many of the patients. We observed the appearance of Bipolar Disorder (BD) in a patient with a previously reported case of TS, who is one of the very few patients to survive childhood. This is most interesting because the common SNP most highly associated with BD is rs1006737, which we show here is a cis-expression quantitative trait locus (eQTL) for CACNA1C in human cerebellum, and the risk allele (A) is associated with decreased expression. To combine the CACNA1C perturbations in the presence of BD in this patient and in patients with the common CACNA1C SNP risk allele, we would propose that either increase or decrease in calcium influx in excitable cells can be associated with BD. In treatment of BD with calcium channel blocking drugs (CCBs), we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.
doi:10.1038/mp.2013.107
PMCID: PMC4151967  PMID: 23979604
Bipolar disorder; Timothy syndrome; calcium channel blockers; CACNA1C; long QT syndrome
2.  Genome-wide Association Study of Obsessive-Compulsive Disorder 
Stewart, S Evelyn | Yu, Dongmei | Scharf, Jeremiah M | Neale, Benjamin M | Fagerness, Jesen A | Mathews, Carol A | Arnold, Paul D | Evans, Patrick D | Gamazon, Eric R | Osiecki, Lisa | McGrath, Lauren | Haddad, Stephen | Crane, Jacquelyn | Hezel, Dianne | Illman, Cornelia | Mayerfeld, Catherine | Konkashbaev, Anuar | Liu, Chunyu | Pluzhnikov, Anna | Tikhomirov, Anna | Edlund, Christopher K | Rauch, Scott L | Moessner, Rainald | Falkai, Peter | Maier, Wolfgang | Ruhrmann, Stephan | Grabe, Hans-Jörgen | Lennertz, Leonard | Wagner, Michael | Bellodi, Laura | Cavallini, Maria Cristina | Richter, Margaret A | Cook, Edwin H | Kennedy, James L | Rosenberg, David | Stein, Dan J | Hemmings, Sian MJ | Lochner, Christine | Azzam, Amin | Chavira, Denise A | Fournier, Eduardo | Garrido, Helena | Sheppard, Brooke | Umaña, Paul | Murphy, Dennis L | Wendland, Jens R | Veenstra-VanderWeele, Jeremy | Denys, Damiaan | Blom, Rianne | Deforce, Dieter | Van Nieuwerburgh, Filip | Westenberg, Herman GM | Walitza, Susanne | Egberts, Karin | Renner, Tobias | Miguel, Euripedes Constantino | Cappi, Carolina | Hounie, Ana G | Conceição do Rosário, Maria | Sampaio, Aline S | Vallada, Homero | Nicolini, Humberto | Lanzagorta, Nuria | Camarena, Beatriz | Delorme, Richard | Leboyer, Marion | Pato, Carlos N | Pato, Michele T | Voyiaziakis, Emanuel | Heutink, Peter | Cath, Danielle C | Posthuma, Danielle | Smit, Jan H | Samuels, Jack | Bienvenu, O Joseph | Cullen, Bernadette | Fyer, Abby J | Grados, Marco A | Greenberg, Benjamin D | McCracken, James T | Riddle, Mark A | Wang, Ying | Coric, Vladimir | Leckman, James F | Bloch, Michael | Pittenger, Christopher | Eapen, Valsamma | Black, Donald W | Ophoff, Roel A | Strengman, Eric | Cusi, Daniele | Turiel, Maurizio | Frau, Francesca | Macciardi, Fabio | Gibbs, J Raphael | Cookson, Mark R | Singleton, Andrew | Hardy, John | Crenshaw, Andrew T | Parkin, Melissa A | Mirel, Daniel B | Conti, David V | Purcell, Shaun | Nestadt, Gerald | Hanna, Gregory L | Jenike, Michael A | Knowles, James A | Cox, Nancy | Pauls, David L
Molecular psychiatry  2012;18(7):788-798.
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1,465 cases, 5,557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9,657 X-chromosome SNPs. Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two p-values were located within DLGAP1 (p=2.49×10-6 and p=3.44×10-6), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a p-value=3.84 × 10-8. However, when trios were meta-analyzed with the combined case-control samples, the p-value for this variant was 3.62×10-5, losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation-QTLs (p<0.001) and frontal lobe eQTLs (p=0.001) was observed within the top-ranked SNPs (p<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
doi:10.1038/mp.2012.85
PMCID: PMC4218751  PMID: 22889921
Obsessive-compulsive disorder; GWAS; Genetic; Genomic; Neurodevelopmental disorder; DLGAP
3.  Association Testing of the Mitochondrial Genome Using Pedigree Data 
Genetic epidemiology  2013;37(3):239-247.
In humans, mitochondria contain their own DNA (mtDNA) that is inherited exclusively from the mother. The mitochondrial genome encodes thirteen polypeptides that are components of oxidative phosphorylation to produce energy. Any disruption in these genes might interfere with energy production and thus contribute to metabolic derangement. Mitochondria also regulate several important cellular activities including cell death and calcium homeostasis. Aided by sharply declining costs of high-density genotyping, hundreds of mitochondrial variants will soon be available in several cohorts with pedigree structures. Association testing of mitochondrial variants with disease traits using pedigree data raises unique challenges because of the difficulty in separating the effects of nuclear and mitochondrial genomes, which display different modes of inheritance. Failing to correctly account for these effects might decrease power or inflate type I error in association tests. In this report, we sought to identify the best strategy for association testing of mitochondrial variants when genotype and phenotype data are available in pedigrees. We proposed several strategies to account for polygenic effects of the nuclear and mitochondrial genomes and we performed extensive simulation studies to evaluate type I error and power of these strategies. In addition, we proposed two permutation tests to obtain empirical p-values for these strategies. Furthermore, we applied two of the analytical strategies to association analysis of 196 mitochondrial variants with blood pressure and fasting blood glucose in the pedigree rich, Framingham Heart Study. Finally, we discussed strategies for study design, genotyping, and data cleaning in association testing of mtDNA in pedigrees.
doi:10.1002/gepi.21706
PMCID: PMC4171957  PMID: 23319385
mitochondrial DNA; association test; polygenic effect; maternal lineage; permutation test
4.  Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors 
A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.
doi:10.2174/1874104501408010023
PMCID: PMC4157350  PMID: 25250097
Betulin derivative; HIV; macrocyclization; maturation inhibitor
5.  Expression of the G72/G30 gene in transgenic mice induces behavioral changes 
Molecular psychiatry  2013;19(2):175-183.
The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, Western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially-expressed in transgenic mice compared to wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders.
doi:10.1038/mp.2012.185
PMCID: PMC3636154  PMID: 23337943
G72/G30; transgenic mouse model; gene expression; stereotypic behavior; hedonic response; psychiatric disorders
6.  Structural Damage Identification Based on Rough Sets and Artificial Neural Network 
The Scientific World Journal  2014;2014:193284.
This paper investigates potential applications of the rough sets (RS) theory and artificial neural network (ANN) method on structural damage detection. An information entropy based discretization algorithm in RS is applied for dimension reduction of the original damage database obtained from finite element analysis (FEA). The proposed approach is tested with a 14-bay steel truss model for structural damage detection. The experimental results show that the damage features can be extracted efficiently from the combined utilization of RS and ANN methods even the volume of measurement data is enormous and with uncertainties.
doi:10.1155/2014/193284
PMCID: PMC4074987  PMID: 25013847
7.  Inference of SNP-Gene Regulatory Networks by Integrating Gene Expressions and Genetic Perturbations 
BioMed Research International  2014;2014:629697.
In order to elucidate the overall relationships between gene expressions and genetic perturbations, we propose a network inference method to infer gene regulatory network where single nucleotide polymorphism (SNP) is involved as a regulator of genes. In the most of the network inferences named as SNP-gene regulatory network (SGRN) inference, pairs of SNP-gene are given by separately performing expression quantitative trait loci (eQTL) mappings. In this paper, we propose a SGRN inference method without predefined eQTL information assuming a gene is regulated by a single SNP at most. To evaluate the performance, the proposed method was applied to random data generated from synthetic networks and parameters. There are three main contributions. First, the proposed method provides both the gene regulatory inference and the eQTL identification. Second, the experimental results demonstrated that integration of multiple methods can produce competitive performances. Lastly, the proposed method was also applied to psychiatric disorder data in order to explore how the method works with real data.
doi:10.1155/2014/629697
PMCID: PMC4127230  PMID: 25136606
8.  Two Gene Co-expression Modules Differentiate Psychotics and Controls 
Molecular psychiatry  2012;18(12):1308-1314.
Schizophrenia and bipolar disorder are highly heritable psychiatric disorders. Associated genetic and gene expression changes have been identified, but many have not been replicated and have unknown functions. We identified groups of genes whose expressions varied together, i.e. co-expression modules, then tested them for association with schizophrenia. Using Weighted Gene Co-expression Network Analysis, we show that two modules were differentially expressed in patients versus controls. One, up-regulated in cerebral cortex, was enriched with neuron differentiation and neuron development genes, as well as disease GWAS genetic signals; the second, altered in cerebral cortex and cerebellum, was enriched with genes involved in neuron protection functions. The findings were preserved in five expression data sets, including sets from three brain regions, from a different microarray platform, and from bipolar disorder patients. From those observations, we propose neuron differentiation and development pathways may be involved in etiologies of both schizophrenia and bipolar disorder, and neuron protection function participates in pathological process of the diseases.
doi:10.1038/mp.2012.146
PMCID: PMC4018461  PMID: 23147385
Gene Expression; Schizophrenia; WGCNA; Neuron differentiation; Neuron protection
9.  Wild-Type Measles Viruses with Non-Standard Genome Lengths 
PLoS ONE  2014;9(4):e95470.
The length of the single stranded, negative sense RNA genome of measles virus (MeV) is highly conserved at 15,894 nucleotides (nt). MeVs can be grouped into 24 genotypes based on the highly variable 450 nucleotides coding for the carboxyl-terminus of the nucleocapsid protein (N-450). Here, we report the genomic sequences of 2 wild-type viral isolates of genotype D4 with genome lengths of 15,900 nt. Both genomes had a 7 nt insertion in the 3′ untranslated region (UTR) of the matrix (M) gene and a 1 nt deletion in the 5′ UTR of the fusion (F) gene. The net gain of 6 nt complies with the rule-of-six required for replication competency of the genomes of morbilliviruses. The insertions and deletion (indels) were confirmed in a patient sample that was the source of one of the viral isolates. The positions of the indels were identical in both viral isolates, even though epidemiological data and the 3 nt differences in N-450 between the two genomes suggested that the viruses represented separate chains of transmission. Identical indels were found in the M-F intergenic regions of 14 additional genotype D4 viral isolates that were imported into the US during 2007–2010. Viral isolates with and without indels produced plaques of similar size and replicated efficiently in A549/hSLAM and Vero/hSLAM cells. This is the first report of wild-type MeVs with genome lengths other than 15,894 nt and demonstrates that the length of the M-F UTR of wild-type MeVs is flexible.
doi:10.1371/journal.pone.0095470
PMCID: PMC3991672  PMID: 24748123
10.  Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder 
Nature Communications  2013;4:2739.
Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10−12 (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08–1.17) across both disorders and Pmeta=2.67 × 10−8 (OR=1.15, 95% CI: 1.08–1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.
Schizophrenia and bipolar disorder are important psychiatric disorders with overlapping genetic components. Here, the authors identify and replicate a genome-wide significant risk locus for the two disorders, and suggest a role for NDST3 in severe psychiatric disease.
doi:10.1038/ncomms3739
PMCID: PMC3905728  PMID: 24253340
11.  Genetic imaging of the association of oxytocin receptor gene (OXTR) polymorphisms with positive maternal parenting 
Background: Well-validated models of maternal behavior in small-brain mammals posit a central role of oxytocin in parenting, by reducing stress and enhancing the reward value of social interactions with offspring. In contrast, human studies are only beginning to gain insights into how oxytocin modulates maternal behavior and affiliation.
Methods: To explore associations between oxytocin receptor genes and maternal parenting behavior in humans, we conducted a genetic imaging study of women selected to exhibit a wide range of observed parenting when their children were 4–6 years old.
Results: In response to child stimuli during functional magnetic resonance imaging (fMRI), hemodynamic responses in brain regions that mediate affect, reward, and social behavior were significantly correlated with observed positive parenting. Furthermore, single nucleotide polymorphisms (SNPs) (rs53576 and rs1042778) in the gene encoding the oxytocin receptor were significantly associated with both positive parenting and hemodynamic responses to child stimuli in orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and hippocampus.
Conclusions: These findings contribute to the emerging literature on the role of oxytocin in human social behavior and support the feasibility of tracing biological pathways from genes to neural regions to positive maternal parenting behaviors in humans using genetic imaging methods.
doi:10.3389/fnbeh.2014.00021
PMCID: PMC3909919  PMID: 24550797
maternal parenting oxytocin receptor gene; functional magnetic resonance imaging
12.  Genome-wide association study of Tourette Syndrome 
Scharf, Jeremiah M. | Yu, Dongmei | Mathews, Carol A. | Neale, Benjamin M. | Stewart, S. Evelyn | Fagerness, Jesen A | Evans, Patrick | Gamazon, Eric | Edlund, Christopher K. | Service, Susan | Tikhomirov, Anna | Osiecki, Lisa | Illmann, Cornelia | Pluzhnikov, Anna | Konkashbaev, Anuar | Davis, Lea K | Han, Buhm | Crane, Jacquelyn | Moorjani, Priya | Crenshaw, Andrew T. | Parkin, Melissa A. | Reus, Victor I. | Lowe, Thomas L. | Rangel-Lugo, Martha | Chouinard, Sylvain | Dion, Yves | Girard, Simon | Cath, Danielle C | Smit, Jan H | King, Robert A. | Fernandez, Thomas | Leckman, James F. | Kidd, Kenneth K. | Kidd, Judith R. | Pakstis, Andrew J. | State, Matthew | Herrera, Luis Diego | Romero, Roxana | Fournier, Eduardo | Sandor, Paul | Barr, Cathy L | Phan, Nam | Gross-Tsur, Varda | Benarroch, Fortu | Pollak, Yehuda | Budman, Cathy L. | Bruun, Ruth D. | Erenberg, Gerald | Naarden, Allan L | Lee, Paul C | Weiss, Nicholas | Kremeyer, Barbara | Berrío, Gabriel Bedoya | Campbell, Desmond | Silgado, Julio C. Cardona | Ochoa, William Cornejo | Restrepo, Sandra C. Mesa | Muller, Heike | Duarte, Ana V. Valencia | Lyon, Gholson J | Leppert, Mark | Morgan, Jubel | Weiss, Robert | Grados, Marco A. | Anderson, Kelley | Davarya, Sarah | Singer, Harvey | Walkup, John | Jankovic, Joseph | Tischfield, Jay A. | Heiman, Gary A. | Gilbert, Donald L. | Hoekstra, Pieter J. | Robertson, Mary M. | Kurlan, Roger | Liu, Chunyu | Gibbs, J. Raphael | Singleton, Andrew | Hardy, John | Strengman, Eric | Ophoff, Roel | Wagner, Michael | Moessner, Rainald | Mirel, Daniel B. | Posthuma, Danielle | Sabatti, Chiara | Eskin, Eleazar | Conti, David V. | Knowles, James A. | Ruiz-Linares, Andres | Rouleau, Guy A. | Purcell, Shaun | Heutink, Peter | Oostra, Ben A. | McMahon, William | Freimer, Nelson | Cox, Nancy J. | Pauls, David L.
Molecular psychiatry  2012;18(6):721-728.
Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.
doi:10.1038/mp.2012.69
PMCID: PMC3605224  PMID: 22889924
Tourette Syndrome; tics; genetics; GWAS; neurodevelopmental disorder
13.  Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture 
Davis, Lea K. | Yu, Dongmei | Keenan, Clare L. | Gamazon, Eric R. | Konkashbaev, Anuar I. | Derks, Eske M. | Neale, Benjamin M. | Yang, Jian | Lee, S. Hong | Evans, Patrick | Barr, Cathy L. | Bellodi, Laura | Benarroch, Fortu | Berrio, Gabriel Bedoya | Bienvenu, Oscar J. | Bloch, Michael H. | Blom, Rianne M. | Bruun, Ruth D. | Budman, Cathy L. | Camarena, Beatriz | Campbell, Desmond | Cappi, Carolina | Cardona Silgado, Julio C. | Cath, Danielle C. | Cavallini, Maria C. | Chavira, Denise A. | Chouinard, Sylvain | Conti, David V. | Cook, Edwin H. | Coric, Vladimir | Cullen, Bernadette A. | Deforce, Dieter | Delorme, Richard | Dion, Yves | Edlund, Christopher K. | Egberts, Karin | Falkai, Peter | Fernandez, Thomas V. | Gallagher, Patience J. | Garrido, Helena | Geller, Daniel | Girard, Simon L. | Grabe, Hans J. | Grados, Marco A. | Greenberg, Benjamin D. | Gross-Tsur, Varda | Haddad, Stephen | Heiman, Gary A. | Hemmings, Sian M. J. | Hounie, Ana G. | Illmann, Cornelia | Jankovic, Joseph | Jenike, Michael A. | Kennedy, James L. | King, Robert A. | Kremeyer, Barbara | Kurlan, Roger | Lanzagorta, Nuria | Leboyer, Marion | Leckman, James F. | Lennertz, Leonhard | Liu, Chunyu | Lochner, Christine | Lowe, Thomas L. | Macciardi, Fabio | McCracken, James T. | McGrath, Lauren M. | Mesa Restrepo, Sandra C. | Moessner, Rainald | Morgan, Jubel | Muller, Heike | Murphy, Dennis L. | Naarden, Allan L. | Ochoa, William Cornejo | Ophoff, Roel A. | Osiecki, Lisa | Pakstis, Andrew J. | Pato, Michele T. | Pato, Carlos N. | Piacentini, John | Pittenger, Christopher | Pollak, Yehuda | Rauch, Scott L. | Renner, Tobias J. | Reus, Victor I. | Richter, Margaret A. | Riddle, Mark A. | Robertson, Mary M. | Romero, Roxana | Rosàrio, Maria C. | Rosenberg, David | Rouleau, Guy A. | Ruhrmann, Stephan | Ruiz-Linares, Andres | Sampaio, Aline S. | Samuels, Jack | Sandor, Paul | Sheppard, Brooke | Singer, Harvey S. | Smit, Jan H. | Stein, Dan J. | Strengman, E. | Tischfield, Jay A. | Valencia Duarte, Ana V. | Vallada, Homero | Van Nieuwerburgh, Filip | Veenstra-VanderWeele, Jeremy | Walitza, Susanne | Wang, Ying | Wendland, Jens R. | Westenberg, Herman G. M. | Shugart, Yin Yao | Miguel, Euripedes C. | McMahon, William | Wagner, Michael | Nicolini, Humberto | Posthuma, Danielle | Hanna, Gregory L. | Heutink, Peter | Denys, Damiaan | Arnold, Paul D. | Oostra, Ben A. | Nestadt, Gerald | Freimer, Nelson B. | Pauls, David L. | Wray, Naomi R. | Stewart, S. Evelyn | Mathews, Carol A. | Knowles, James A. | Cox, Nancy J. | Scharf, Jeremiah M.
PLoS Genetics  2013;9(10):e1003864.
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Author Summary
Family and twin studies have shown that genetic risk factors are important in the development of Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). However, efforts to identify the individual genetic risk factors involved in these two neuropsychiatric disorders have been largely unsuccessful. One possible explanation for this is that many genetic variations scattered throughout the genome each contribute a small amount to the overall risk. For TS and OCD, the genetic architecture (characterized by the number, frequency, and distribution of genetic risk factors) is presently unknown. This study examined the genetic architecture of TS and OCD in a variety of ways. We found that rare genetic changes account for more genetic risk in TS than in OCD; certain chromosomes contribute to OCD risk more than others; and variants that influence the level of genes expressed in two regions of the brain can account for a significant amount of risk for both TS and OCD. Results from this study might help in determining where, and what kind of variants are individual risk factors for TS and OCD and where they might be located in the human genome.
doi:10.1371/journal.pgen.1003864
PMCID: PMC3812053  PMID: 24204291
14.  Galectin-3, a Marker of Cardiac Fibrosis, Predicts Incident Heart Failure in the Community 
Objectives
We sought to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community.
Background
Gal-3 is an emerging prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown.
Methods
Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years, 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression.
Results
Gal-3 was associated with increased left ventricular mass in age- and sex-adjusted analyses (P=0.001); this association was attenuated in multivariable analyses (P=0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up of 8.1 years. Gal-3 was associated with risk of incident HF (HR 1.28 per 1 standard deviation increase in log-Gal-3, 95% CI 1.14–1.43, P<0.0001), and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR 1.23, 95% CI 1.04–1.47, P=0.02). Gal-3 was also associated with risk of all-cause mortality (multivariable-adjusted HR 1.15, 95% CI 1.04–1.28, P=0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the c-statistic and minor improvements in the net reclassification index.
Conclusions
Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk of incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF.
doi:10.1016/j.jacc.2012.04.053
PMCID: PMC3512095  PMID: 22939561
heart failure; epidemiology; biomarker; prognosis
15.  Association of Genetic Variation in the Mitochondrial Genome with Blood Pressure and Metabolic Traits 
Hypertension  2012;60(4):949-956.
Elevated blood pressure (BP) is a major risk factor for cardiovascular disease. Several studies have noted a consistent maternal effect on BP; consequently, mitochondrial DNA (mtDNA) variation has become an additional target of investigation of the missing BP heritability. Analyses of common mtDNA polymorphisms, however, have not found evidence of association with hypertension. To explore associations of relatively rare (frequency < 5%) mtDNA variants with BP, we identified uncommon/rare variants through sequencing the entire mitochondrial genome in 32 unrelated individuals with extreme-high BP in the Framingham Heart Study (FHS) and genotyped 40 mtSNPs in 7,219 FHS participants. The nonsynonymous mtSNP 5913G>A (Asp4Asn) in the cytochrome c oxidase subunit 1 of Complex IV demonstrated significant associations with BP and fasting blood glucose (FBG) levels. Individuals with the rare 5913A allele had, on average, 7 mm Hg higher systolic BP at baseline (Pempirical = 0.05) and 17 mg/dL higher mean FBG over 25 years of follow up (Pempirical = 0.009). Significant associations with FBG levels were also detected for nonsynonymous mtSNP 3316G>A (Ala4Thr) in the NADH dehydrogenase subunit 1 of Complex I. On average, individuals with rare allele 3316A had 17 and 25 mg/dL higher FBG at baseline (Pempirical = 0.01) and over 25 years of follow up (Pempirical = 0.007). Our findings provide the first evidence of putative association of variants in the mitochondrial genome with SBP and FBG in the general population. Replication in independent samples, however, is needed to confirm these putative associations.
doi:10.1161/HYPERTENSIONAHA.112.196519
PMCID: PMC3753106  PMID: 22949535
Mitochondrial genome; Association study; Genetics; Hypertension; Diabetes
16.  Genetic Characterization of the Hemagglutinin Genes of Wild-Type Measles Virus Circulating in China, 1993–2009 
PLoS ONE  2013;8(9):e73374.
Background
China experienced several large measles outbreaks in the past two decades, and a series of enhanced control measures were implemented to achieve the goal of measles elimination. Molecular epidemiologic surveillance of wild-type measles viruses (MeV) provides valuable information about the viral transmission patterns. Since 1993, virologic surveillnace has confirmed that a single endemic genotype H1 viruses have been predominantly circulating in China. A component of molecular surveillance is to monitor the genetic characteristics of the hemagglutinin (H) gene of MeV, the major target for virus neutralizing antibodies.
Principal Findings
Analysis of the sequences of the complete H gene from 56 representative wild-type MeV strains circulating in China during 1993–2009 showed that the H gene sequences were clustered into 2 groups, cluster 1 and cluster 2. Cluster1 strains were the most frequently detected cluster and had a widespread distribution in China after 2000. The predicted amino acid sequences of the H protein were relatively conserved at most of the functionally significant amino acid positions. However, most of the genotype H1 cluster1 viruses had an amino acid substitution (Ser240Asn), which removed a predicted N-linked glycosylation site. In addition, the substitution of Pro397Leu in the hemagglutinin noose epitope (HNE) was identified in 23 of 56 strains. The evolutionary rate of the H gene of the genotype H1 viruses was estimated to be approximately 0.76×10−3 substitutions per site per year, and the ratio of dN to dS (dN/dS) was <1 indicating the absence of selective pressure.
Conclusions
Although H genes of the genotype H1 strains were conserved and not subjected to selective pressure, several amino acid substitutions were observed in functionally important positions. Therefore the antigenic and genetic properties of H genes of wild-type MeVs should be monitored as part of routine molecular surveillance for measles in China.
doi:10.1371/journal.pone.0073374
PMCID: PMC3779233  PMID: 24073194
17.  Preliminary Genetic Imaging Study of the Association between Estrogen Receptor-α Gene Polymorphisms and Harsh Human Maternal Parenting 
Neuroscience letters  2012;525(1):17-22.
A failure of neural changes initiated by the estrogen surge in late pregnancy to reverse the valence of infant stimuli from aversive to rewarding is associated with dysfunctional maternal behavior in nonhuman mammals. Estrogen receptor-α plays the crucial role in mediating these neural effects of estrogen priming. This preliminary study examines associations between estrogen receptor-α gene polymorphisms and human maternal behavior. Two polymorphisms were associated with human negative maternal parenting. Furthermore, hemodynamic responses in functional magnetic resonance imaging to child stimuli in neural regions associated with social cognition fully mediated the association between genetic variation and negative parenting. This suggests testable hypotheses regarding a biological pathway between genetic variants and dysfunctional human maternal parenting.
doi:10.1016/j.neulet.2012.07.016
PMCID: PMC3434869  PMID: 22819972
Estrogen receptor-α; ESR1; maternal parenting; functional magnetic resonance imaging
18.  Orthostatic hypotension and novel blood pressure-associated gene variants: Genetics of Postural Hemodynamics (GPH) Consortium 
European Heart Journal  2012;33(18):2331-2341.
Aims
Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown.
Methods and results
A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8%) met the diagnostic criteria for OH (systolic/diastolic BP drop ≥20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95% confidence interval: 0.90, 0.85–0.96; P = 0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75–0.95; P = 0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.87–0.98; P= 0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.02–1.24; P = 0.02, rs198358: 1.10, 1.01–1.20; P = 0.04, and rs5068: 1.22, 1.04–1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P= 0.04).
Conclusion
The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.
doi:10.1093/eurheartj/ehs058
PMCID: PMC3442958  PMID: 22504314
Orthostatic hypotension; Genetics; Single nucleotide polymorphism; Steroid 17-alpha-hydroxylase; Natriuretic peptides; Adrenomedullin
19.  Ordered Stratification to Reduce Heterogeneity in Linkage to Diabetes-Related Quantitative Traits 
Obesity (Silver Spring, Md.)  2008;16(10):2314-2322.
Phenotypic heterogeneity complicates detection of genomic loci predisposing to type 2 diabetes, potentially obscuring or unmasking specific loci. We conducted ordered subsets linkage analyses (OSA) for diabetes-related quantitative traits (fasting insulin and glucose, HbA1c and 28-year time averaged fasting plasma glucose (tFPG)) from 330 families of the Framingham Offspring Study. We calculated mean body mass index (BMI), waist circumference (WC), and a diabetes ‘age-of-onset score’ for each family. We constructed subsets by adding one family at a time in increasing (lean family to obese) or decreasing (obese to lean) adiposity order or increasing or decreasing propensity to develop diabetes at a younger age, with the OSA LOD reported as the maximum LOD observed in any subset. Permutation p-values tested the hypothesis that phenotypic ordering showed stronger linkage than random ordering. On chromosome 1, ordering by increasing family mean WC increased linkage to tFPG at 256 cM from LOD = 2.4 to 3.5 (permuted p=0.02) and to HbA1c at 180 cM from LOD = 2.0 to 3.3 (p=0.01). On chromosome 19, ordering by decreasing WC increased linkage to fasting insulin at 68 cM from LOD = 2.7 to 4.6 (p=0.002), and ordering by decreasing propensity to develop diabetes at a young age increased linkage to fasting insulin at 73 cM from LOD = 2.7 to 4.0 (p=0.046). We conclude that chromosomes 1 and 19 could harbor adiposity-interacting diabetes susceptibility genes. Such interactions might also influence trait-locus associations and may be useful to consider in diabetes genome-wide association studies.
doi:10.1038/oby.2008.354
PMCID: PMC3747653  PMID: 18719643
type 2 diabetes mellitus; insulin resistance; genetics; risk factors; longitudinal study; linkage study; genetics; genomics
20.  Selection of the Most Informative Individuals from Families with Multiple Siblings for Association Studies 
Genetic epidemiology  2009;33(4):299-307.
Association analyses may follow an initial linkage analysis for mapping and identifying genes underlying complex quantitative traits and may be conducted on unrelated subsets of individuals where only one member of a family is included. We evaluate two methods to select one sibling per sibship when multiple siblings are available: 1) one sibling with the most extreme trait value; and 2) one sibling using a combination score statistic based on extreme trait values and identity-by-descent sharing information. We compare the type I error and power. Furthermore, we compare these selection strategies with a strategy that randomly selects one sibling per sibship and with an approach that includes all siblings, using both simulation study and an application to fasting blood glucose in the Framingham Heart Study. When genetic effect is homogeneous, we find that using the combination score can increase power by 30 to 40% compared to a random selection strategy, and loses only 8 ~ 13% of power compared to the full sibship analysis, across all additive models considered, but offers at least 50% genotyping cost saving. In the presence of genetic heterogeneity, the score offers a 50% increase in power over a random selection strategy, but there is substantial loss compared to the full sibship analysis. In application to fasting blood sample, two SNPs are found in common for the selection strategies and the full sample among the 10 highest ranked SNPs. The EV strategy tends to agree with the IBD-EV strategy and the analysis of the full sample.
doi:10.1002/gepi.20380
PMCID: PMC3747668  PMID: 19025786
linkage analysis; association study; linkage disequilibrium; identity-by-descent (IBD)
21.  Large Genomic Region Free of GWAS-Based Common Variants Contains Fertility-Related Genes 
PLoS ONE  2013;8(4):e61917.
DNA variants, such as single nucleotide polymorphisms (SNPs) and copy number variants (CNVs), are unevenly distributed across the human genome. Currently, dbSNP contains more than 6 million human SNPs, and whole-genome genotyping arrays can assay more than 4 million of them simultaneously. In our study, we first questioned whether published genome-wide association studies (GWASs) assays cover all regions well in the genome. Using dbSNP build 135 data, we identified 50 genomic regions longer than 100 Kb that do not contain any common SNPs, i.e., those with minor allele frequency (MAF)≥1%. Secondly, because conserved regions are generally of functional importance, we tested genes in those large genomic regions without common SNPs. We found 97 genes and were enriched for reproduction function. In addition, we further filtered out regions with CNVs listed in the Database of Genomic Variants (DGV), segmental duplications from Human Genome Project and common variants identified by personal genome sequencing (UCSC). No region survived after those filtering. Our analysis suggests that, while there may not be many large genomic regions free of common variants, there are still some “holes” in the current human genomic map for common SNPs. Because GWAS only focused on common SNPs, interpretation of GWAS results should take this limitation into account. Particularly, two recent GWAS of fertility may be incomplete due to the map deficit. Additional SNP discovery efforts should pay close attention to these regions.
doi:10.1371/journal.pone.0061917
PMCID: PMC3629113  PMID: 23613972
22.  A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function 
Porcu, Eleonora | Medici, Marco | Pistis, Giorgio | Volpato, Claudia B. | Wilson, Scott G. | Cappola, Anne R. | Bos, Steffan D. | Deelen, Joris | den Heijer, Martin | Freathy, Rachel M. | Lahti, Jari | Liu, Chunyu | Lopez, Lorna M. | Nolte, Ilja M. | O'Connell, Jeffrey R. | Tanaka, Toshiko | Trompet, Stella | Arnold, Alice | Bandinelli, Stefania | Beekman, Marian | Böhringer, Stefan | Brown, Suzanne J. | Buckley, Brendan M. | Camaschella, Clara | de Craen, Anton J. M. | Davies, Gail | de Visser, Marieke C. H. | Ford, Ian | Forsen, Tom | Frayling, Timothy M. | Fugazzola, Laura | Gögele, Martin | Hattersley, Andrew T. | Hermus, Ad R. | Hofman, Albert | Houwing-Duistermaat, Jeanine J. | Jensen, Richard A. | Kajantie, Eero | Kloppenburg, Margreet | Lim, Ee M. | Masciullo, Corrado | Mariotti, Stefano | Minelli, Cosetta | Mitchell, Braxton D. | Nagaraja, Ramaiah | Netea-Maier, Romana T. | Palotie, Aarno | Persani, Luca | Piras, Maria G. | Psaty, Bruce M. | Räikkönen, Katri | Richards, J. Brent | Rivadeneira, Fernando | Sala, Cinzia | Sabra, Mona M. | Sattar, Naveed | Shields, Beverley M. | Soranzo, Nicole | Starr, John M. | Stott, David J. | Sweep, Fred C. G. J. | Usala, Gianluca | van der Klauw, Melanie M. | van Heemst, Diana | van Mullem, Alies | H.Vermeulen, Sita | Visser, W. Edward | Walsh, John P. | Westendorp, Rudi G. J. | Widen, Elisabeth | Zhai, Guangju | Cucca, Francesco | Deary, Ian J. | Eriksson, Johan G. | Ferrucci, Luigi | Fox, Caroline S. | Jukema, J. Wouter | Kiemeney, Lambertus A. | Pramstaller, Peter P. | Schlessinger, David | Shuldiner, Alan R. | Slagboom, Eline P. | Uitterlinden, André G. | Vaidya, Bijay | Visser, Theo J. | Wolffenbuttel, Bruce H. R. | Meulenbelt, Ingrid | Rotter, Jerome I. | Spector, Tim D. | Hicks, Andrew A. | Toniolo, Daniela | Sanna, Serena | Peeters, Robin P. | Naitza, Silvia
PLoS Genetics  2013;9(2):e1003266.
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
Author Summary
Levels of thyroid hormones are tightly regulated by TSH produced in the pituitary, and even mild alterations in their concentrations are strong indicators of thyroid pathologies, which are very common worldwide. To identify common genetic variants associated with the highly heritable markers of thyroid function, TSH and FT4, we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function. Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH (within the PDE8B gene and near CAPZB, MAF/LOC440389, and NR3C2) and FT4 (within DIO1) levels. Gender-specific differences in the genetic effects of several variants for TSH and FT4 levels were identified at several loci, which offer clues to understand the known sexual dimorphism in thyroid function and pathology. Of particular clinical interest, we show that TSH-associated loci contribute not only to normal variation, but also to TSH values outside reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings add to the developing landscape of the regulation of thyroid homeostasis and the consequences of genetic variation for thyroid related diseases.
doi:10.1371/journal.pgen.1003266
PMCID: PMC3567175  PMID: 23408906
23.  Emergence and Continuous Evolution of Genotype 1E Rubella Viruses in China 
Journal of Clinical Microbiology  2012;50(2):353-363.
In China, rubella vaccination was introduced into the national immunization program in 2008, and a rubella epidemic occurred in the same year. In order to know whether changes in the genotypic distribution of rubella viruses have occurred in the postvaccination era, we investigate in detail the epidemiological profile of rubella in China and estimate the evolutionary rate, molecular clock phylogeny, and demographic history of the predominant rubella virus genotypes circulating in China using Bayesian Markov chain Monte Carlo phylodynamic analyses. 1E was found to be the predominant rubella virus genotype since its initial isolation in China in 2001, and no genotypic shift has occurred since then. The results suggest that the global 1E genotype may have diverged in 1995 and that it has evolved at a mutation rate of 1.65 × 10−3 per site per year. The Chinese 1E rubella virus isolates were grouped into either cluster 1 or cluster 2, which likely originated in 1997 and 2006, respectively. Cluster 1 viruses were found in all provinces examined in this study and had a mutation rate of 1.90 × 10−3 per site per year. The effective number of infections remained constant until 2007, and along with the introduction of rubella vaccine into the national immunization program, although the circulation of cluster 1 viruses has not been interrupted, some viral lineages have disappeared, and the epidemic started a decline that led to a decrease in the effective population size. Cluster 2 viruses were found only in Hainan Province, likely because of importation.
doi:10.1128/JCM.01264-11
PMCID: PMC3264136  PMID: 22162559
24.  Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci 
Molecular Autism  2012;3:3.
Background
Autism spectrum disorder is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for an association of common variants with autism susceptibility risk have met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum.
Methods
In this study, we utilized publically available genome-wide association study data from the Autism Genome Project and annotated the results (P <0.001) for expression quantitative trait loci present in the parietal lobe (GSE35977), cerebellum (GSE35974) and lymphoblastoid cell lines (GSE7761). We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency to generate an empirical P-value indicating statistically significant enrichment of expression quantitative trait loci in top results from the autism genome-wide association study.
Results
Our findings show a global enrichment of brain expression quantitative trait loci, but not lymphoblastoid cell line expression quantitative trait loci, among top single nucleotide polymorphisms from an autism genome-wide association study. Additionally, the data implicates individual genes SLC25A12, PANX1 and PANX2 as well as pathways previously implicated in autism.
Conclusions
These findings provide supportive rationale for the use of annotation-based approaches to genome-wide association studies.
doi:10.1186/2040-2392-3-3
PMCID: PMC3484025  PMID: 22591576
Autism; annotation; cerebellum; enrichment; expression quantitative trait (eQTL); GWAS; LCL; pannexin; parietal; SLC25A12
25.  Single Endemic Genotype of Measles Virus Continuously Circulating in China for at Least 16 Years 
PLoS ONE  2012;7(4):e34401.
The incidence of measles in China from 1991 to 2008 was reviewed, and the nucleotide sequences from 1507 measles viruses (MeV) isolated during 1993 to 2008 were phylogenetically analyzed. The results showed that measles epidemics peaked approximately every 3 to 5 years with the range of measles cases detected between 56,850 and 140,048 per year. The Chinese MeV strains represented three genotypes; 1501 H1, 1 H2 and 5 A. Genotype H1 was the predominant genotype throughout China continuously circulating for at least 16 years. Genotype H1 sequences could be divided into two distinct clusters, H1a and H1b. A 4.2% average nucleotide divergence was found between the H1a and H1b clusters, and the nucleotide sequence and predicted amino acid homologies of H1a viruses were 92.3%–100% and 84.7%–100%, H1b were 97.1%–100% and 95.3%–100%, respectively. Viruses from both clusters were distributed throughout China with no apparent geographic restriction and multiple co-circulating lineages were present in many provinces. Cluster H1a and H1b viruses were co-circulating during 1993 to 2005, while no H1b viruses were detected after 2005 and the transmission of that cluster has presumably been interrupted. Analysis of the nucleotide and predicted amino acid changes in the N proteins of H1a and H1b viruses showed no evidence of selective pressure. This study investigated the genotype and cluster distribution of MeV in China over a 16-year period to establish a genetic baseline before MeV elimination in Western Pacific Region (WPR). Continuous and extensive MeV surveillance and the ability to quickly identify imported cases of measles will become more critical as measles elimination goals are achieved in China in the near future. This is the first report that a single endemic genotype of measles virus has been found to be continuously circulating in one country for at least 16 years.
doi:10.1371/journal.pone.0034401
PMCID: PMC3332093  PMID: 22532829

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