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1.  Identifying Genetic Variants for Addiction via Propensity Score Adjusted Generalized Kendall’s Tau 
Identifying replicable genetic variants for addiction has been extremely challenging. Besides the common difficulties with genome-wide association studies (GWAS), environmental factors are known to be critical to addiction, and comorbidity is widely observed. Despite the importance of environmental factors and comorbidity for addiction study, few GWAS analyses adequately considered them due to the limitations of the existing statistical methods. Although parametric methods have been developed to adjust for covariates in association analysis, difficulties arise when the traits are multivariate because there is no ready-to-use model for them. Recent nonparametric development includes U-statistics to measure the phenotype-genotype association weighted by a similarity score of covariates. However, it is not clear how to optimize the similarity score. Therefore, we propose a semiparametric method to measure the association adjusted by covariates. In our approach, the nonparametric U-statistic is adjusted by parametric estimates of propensity scores using the idea of inverse probability weighting. The new measurement is shown to be asymptotically unbiased under our null hypothesis while the previous non-weighted and weighted ones are not. Simulation results show that our test improves power as opposed to the non-weighted and two other weighted U-statistic methods, and it is particularly powerful for detecting gene-environment interactions. Finally, we apply our proposed test to the Study of Addiction: Genetics and Environment (SAGE) to identify genetic variants for addiction. Novel genetic variants are found from our analysis, which warrant further investigation in the future.
PMCID: PMC4219655  PMID: 25382885
Addiction; Comorbidity; Genome-wide association study; Inverse probability weighting; Substance dependence
2.  A phylo-functional core of gut microbiota in healthy young Chinese cohorts across lifestyles, geography and ethnicities 
The ISME Journal  2015;9(9):1979-1990.
Structural profiling of healthy human gut microbiota across heterogeneous populations is necessary for benchmarking and characterizing the potential ecosystem services provided by particular gut symbionts for maintaining the health of their hosts. Here we performed a large structural survey of fecal microbiota in 314 healthy young adults, covering 20 rural and urban cohorts from 7 ethnic groups living in 9 provinces throughout China. Canonical analysis of unweighted UniFrac principal coordinates clustered the subjects mainly by their ethnicities/geography and less so by lifestyles. Nine predominant genera, all of which are known to contain short-chain fatty acid producers, co-occurred in all individuals and collectively represented nearly half of the total sequences. Interestingly, species-level compositional profiles within these nine genera still discriminated the subjects according to their ethnicities/geography and lifestyles. Therefore, a phylogenetically diverse core of gut microbiota at the genus level may be commonly shared by distinctive healthy populations as functionally indispensable ecosystem service providers for the hosts.
PMCID: PMC4542028  PMID: 25647347
3.  The evolution and population structure of Lactobacillus fermentum from different naturally fermented products as determined by multilocus sequence typing (MLST) 
BMC Microbiology  2015;15:107.
Lactobacillus fermentum is economically important in the production and preservation of fermented foods. A repeatable and discriminative typing method was devised to characterize L. fermentum at the molecular level. The multilocus sequence typing (MLST) scheme developed was based on analysis of the internal sequence of 11 housekeeping gene fragments (clpX, dnaA, dnaK, groEL, murC, murE, pepX, pyrG, recA, rpoB, and uvrC).
MLST analysis of 203 isolates of L. fermentum from Mongolia and seven provinces/ autonomous regions in China identified 57 sequence types (ST), 27 of which were represented by only a single isolate, indicating high genetic diversity. Phylogenetic analyses based on the sequence of the 11 housekeeping gene fragments indicated that the L. fermentum isolates analyzed belonged to two major groups. A standardized index of association (IAS) indicated a weak clonal population structure in L. fermentum. Split decomposition analysis indicated that recombination played an important role in generating the genetic diversity observed in L. fermentum. The results from the minimum spanning tree strongly suggested that evolution of L. fermentum STs was not correlated with geography or food-type.
The MLST scheme developed will be valuable for further studies on the evolution and population structure of L. fermentum isolates used in food products.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-015-0447-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4437502  PMID: 25990318
Lactobacillus fermentum; multilocus sequence typing (MLST); Population structure; Traditional Fermented food; Sequence type (ST); Housekeeping gene
4.  Maternal race, demography and health care disparities impact risk for IVH in preterm neonates 
The Journal of pediatrics  2014;164(5):1005-1011.e3.
To determine whether risk factors associated with Grade (Gr) 2–4 intraventricular hemorrhage (IVH) differs between African ancestry and white subjects.
Study design
Inborn, appropriate for gestational age (GA) infants with birth weights (BW) 500–1250 grams and exposed to >1 dose of antenatal steroids were enrolled in 24 neonatal intensive care units. Cases had Gr 2–4 IVH and controls matched for site, race and BW range had 2 normal ultrasounds read centrally. Multivariate logistic regression modeling identified factors associated with IVH across African ancestry and white race.
Subjects included 579 African ancestry or white race infants with Gr 2–4 IVH and 532 controls. Mothers of African ancestry children were less educated, and white case mothers were more likely to have > 1 prenatal visit and have a multiple gestation (P ≤.01 for all). Increasing GA (P =.01), preeclampsia (P < .001), complete antenatal steroid exposure (P = .02), cesarean delivery (P < .001) and white race (P = .01) were associated with decreased risk for IVH. Chorioamnionitis (P = .01), Apgar< 3 at 5 min (P < .004), surfactant (P < .001) and high frequency ventilation (P < .001) were associated with increased risk for IVH. Among African ancestry infants, having >1 prenatal visit was associated with decreased risk (P = .02). Among white infants, multiple gestation was associated with increased risk (P < .001) and higher maternal education with decreased IVH risk (P < .05).
Risk for IVH differs between African ancestry and white infants and may be attributable to both race and health care disparities.
PMCID: PMC4095864  PMID: 24589078
preterm infant; intraventricular hemorrhage; race; multiple gestation; prenatal care
5.  High-throughput sequencing for the detection of the bacterial and fungal diversity in Mongolian naturally fermented cow’s milk in Russia 
BMC Microbiology  2015;15:45.
Traditional fermented dairy products are major components of the typical Mongolian diet since ancient times. However, almost all the previous studies on the microbial composition of traditional Mongolian fermented dairy products analyzed food samples from the Chinese Mongolian region and Mongolia but not the Russian Mongolian region. In this study, the bacterial and fungal community diversity of nineteen naturally fermented cow’s milk (NFCM) samples from local Mongolian families residing in Kalmykia and Chita of Russia was investigated with pyrosequencing.
Firmicutes and Ascomycota were the predominant phyla respectively for bacteria and fungi. The abundance of the bacterial phylum Acidobacteria was considerably different between the samples from the two regions. At genus level, Lactobacillus and Pichia were the predominating bacterial and fungal genera, respectively, while six bacterial genera significantly differed between the Kalmykia (enrichment of Aeromonas, Bacillus, Clostridium, Streptococcus, Vogesella) and Chita (enrichment of Lactococcus) samples. The results of principal coordinate analysis (PCoA) based on the bacterial or fungal composition of the Kalmykia and Chita samples revealed a different microbiota structure between the samples collected in these two locations. The redundancy analysis (RDA) identified 60 bacterial and 21 fungal OTUs as the key variables responsible for such microbiota structural difference.
Our results suggest that structural differences existed in the microbiota of NFCM between Kalmykia and Chita. The difference in geographic environment may be an important factor influencing the microbial diversity of NFCM made by the Mongolians in Russia.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-015-0385-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4345014  PMID: 25887414
Pyrosequencing; Naturally fermented cow’s milk; Russia; Kalmykia; Chita; Mongolia
6.  Comparative Genomic Analysis of 45 Type Strains of the Genus Bifidobacterium: A Snapshot of Its Genetic Diversity and Evolution 
PLoS ONE  2015;10(2):e0117912.
Bifidobacteria are well known for their human health-promoting effects and are therefore widely applied in the food industry. Members of the Bifidobacterium genus were first identified from the human gastrointestinal tract and were then found to be widely distributed across various ecological niches. Although the genetic diversity of Bifidobacterium has been determined based on several marker genes or a few genomes, the global diversity and evolution scenario for the entire genus remain unresolved. The present study comparatively analyzed the genomes of 45 type strains. We built a robust genealogy for Bifidobacterium based on 402 core genes and defined its root according to the phylogeny of the tree of bacteria. Our results support that all human isolates are of younger lineages, and although species isolated from bees dominate the more ancient lineages, the bee was not necessarily the original host for bifidobacteria. Moreover, the species isolated from different hosts are enriched with specific gene sets, suggesting host-specific adaptation. Notably, bee-specific genes are strongly associated with respiratory metabolism and are potential in helping those bacteria adapt to the oxygen-rich gut environment in bees. This study provides a snapshot of the genetic diversity and evolution of Bifidobacterium, paving the way for future studies on the taxonomy and functional genomics of the genus.
PMCID: PMC4319941  PMID: 25658111
7.  Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome 
The New England journal of medicine  2014;371(2):119-129.
Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes.
In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period.
Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P = 0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P = 0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups.
As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; number, NCT00719186.)
PMCID: PMC4175743  PMID: 25006718
8.  Rare SERINC2 variants are specific for alcohol dependence in subjects of European descent 
Pharmacogenetics and genomics  2013;23(8):395-402.
We previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in the subjects of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF) < 0.05] in the NKAIN1-SERINC2 region, in order to confirm our previous finding.
A discovery sample (1,409 European-American cases with alcohol dependence and 1,518 European-American controls) and a replication sample (6,438 European-Australian family subjects with 1,645 alcohol dependent probands) underwent association analysis. A total of 39,903 subjects from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 SNPs in the subjects with European descent and about 450 SNPs in the subjects with African descent with 0
Using a weighted regression analysis implemented in the program SCORE-Seq, we found a rare variant constellation across the entire NKAIN1-SERINC2 region that was associated with alcohol dependence in European-Americans (Fp: overall p=1.8×10−4; VT: overall p=1.4×10−4; Collapsing p=6.5×10−5) and European-Australians (Fp: overall p=0.028; Collapsing p=0.025), but not African-Americans, and not associated with any other disorder examined. Association signals in this region came mainly from SERINC2, a gene that codes for an activity-regulated protein expressed in brain that incorporates serine into lipids. Additionally, 26 individual rare variants were nominally associated with alcohol dependence in European-Americans (p<0.05). The associations of 5 of these rare variants that lay within SERINC2 exhibited region-wide significance (p<α=0.0006); and 25 associations survived correction for false discovery rate (q<0.05). The associations of 2 rare variants at SERINC2 were replicated in European-Australians (p<0.05).
We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in the subjects of European descent.
PMCID: PMC4287355  PMID: 23778322
SERINC2; alcohol dependence; rare variant constellations; European descent; association
Fertility and sterility  2013;101(1):258-269.e8.
To summarize baseline characteristics from a large multi-center infertility clinical trial.
Cross-sectional baseline data from a double-blind randomized trial of 2 treatment regimens (letrozole vs. clomiphene).
Academic Health Centers throughout the U.S.
Main Outcome Measure(s)
Historical, biometric, biochemical and questionnaire parameters.
750 women with PCOS and their male partners took part in the study.
Females averaged ~30 years old and were obese (BMI 35) with ~20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). . Most of the females had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH:FSH ratio (~2), and AMH levels (8.0 ng/mL). Additionally, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH:FSH levels, AMH levels and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Males were obese (BMI 30) and had normal mean semen parameters.
The treatment groups were well-matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators.
PMCID: PMC3899700  PMID: 24156957
insulin resistance; hirsutism; infertility; ovulation induction; metabolic syndrome
Psychiatric genetics  2013;23(6):233-238.
Alcohol dependence is more common among men than among women. Potential explanations for this male excess include a role of genes on sex chromosomes (X and Y). In the present study, we scanned the entire Y chromosome and its homologues on X chromosome in males, in order to identify male-specific risk genes for alcohol dependence. Two thousand nine hundred twenty-seven subjects in two independent cohorts were analyzed. The European-American male cohort [883 cases with alcohol dependence and 445 controls] served as the discovery cohort and the European-American female cohort [526 cases and 1,073 controls] served as a contrast group. All subjects were genotyped on the Illumina Human 1M beadchip. Two thousand two hundred twenty-four SNPs on Y chromosome or in the homologues on X chromosome were analyzed. The allele frequencies were compared between cases and controls within each cohort using logistic regression analysis. We found that, after experiment-wide correction, 2 SNPs on the X chromosome were significantly associated with alcohol dependence in European-American males (p=1.0×10-4 for rs5916144 and p=5.5×10−5 for rs5961794 at 3'UTR of NLGN4X), but not in females. A total of twenty-six SNPs at 3'UTR of or within NLGN4X were nominally associated with alcohol dependence in males (5.5×10−5≤p≤p0.05), all of which were not statistically significant in females. We conclude that NLGN4X was a significant male-specific risk gene for alcohol dependence in European-Americans. NLGN4X might harbor a causal variant(s) for alcohol dependence. A defect of synaptogenesis in neuronal circuitry caused by NLGN4X mutations is believed to play a role in alcohol dependence.
PMCID: PMC3941913  PMID: 23907288
Alcohol dependence; NLGN4X; Y chromosome; Homologue; Male-specificity; Synaptogenesis
The Journal of pediatrics  2013;163(5):10.1016/j.jpeds.2013.06.025.
Intraventricular hemorrhage is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and Grade 3-4 intraventricular hemorrhage and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of intraventricular hemorrhage, emphasizing the need for more comprehensive genetic strategies.
PMCID: PMC3812267  PMID: 23896193
In genetic studies of complex diseases, particularly mental illnesses, and behavior disorders, two distinct characteristics have emerged in some data sets. First, genetic data sets are collected with a large number of phenotypes that are potentially related to the complex disease under study. Second, each phenotype is collected from the same subject repeatedly over time. In this study, we present a nonparametric regression approach to study multivariate and time-repeated phenotypes together by using the technique of the multivariate adaptive regression splines for analysis of longitudinal data (MASAL), which makes it possible to identify genes, gene-gene and gene-environment, including time, interactions associated with the phenotypes of interest. Furthermore, we propose a permutation test to assess the associations between the phenotypes and selected markers. Through simulation, we demonstrate that our proposed approach has advantages over the existing methods that examine each longitudinal phenotype separately or analyze the summarized values of phenotypes by compressing them into one-time-point phenotypes. Application of the proposed method to the Framingham Heart Study illustrates that the use of multivariate longitudinal phenotypes enhanced the significance of the association test.
PMCID: PMC4193387  PMID: 25309585
Multivariate phenotypes; longitudinal data analysis; genetic association test; multivariate adaptive regression splines
Background and Objectives
We previously reported a risk genomic region (i.e., PTP4A1-PHF3-EYS) for alcohol dependence in a genome-wide association study (GWAS). We also reported a rare variant constellation across this region that was significantly associated with alcohol dependence. In the present study, we significantly increased the marker density within this region and examined the specificity of the associations of common variants for alcohol dependence.
One African-American discovery sample (681 cases with alcohol dependence and 508 controls), one European-American replication sample (1,409 alcohol dependent cases and 1,518 controls), and one European-Australian replication sample (a total of 6,438 family subjects with 1,645 alcohol dependent probands) underwent association analysis. A total of 38,714 subjects from 18 other cohorts with 10 different neuropsychiatric disorders served as contrast groups.
We found 289 SNPs that were nominally associated with alcohol dependence in the discovery sample (p<0.05). Fifty-six associations of them were significant after correction (1.9×10-6≤p≤1.6×10-5). No markers were significantly associated with other neuropsychiatric disorders after experiment-wide correction.
Conclusions and Scientific Significance
We confirmed with our previous findings that PTP4A1-PHF3-EYS variants were significantly associated with alcohol dependence, which were replicable across multiple independent populations and were specific for alcohol dependence. These findings suggested that this region might harbor a causal variant(s) for alcohol dependence.
PMCID: PMC4111256  PMID: 24961364
Common variants; Alcohol dependence; PTP4A1; PHF3; EYS
Scientific Reports  2014;4:5654.
Gut microbiota mediated low-grade inflammation is involved in the onset of type 2 diabetes (T2DM). In this study, we used a high fat sucrose (HFS) diet-induced pre-insulin resistance and a low dose-STZ HFS rat models to study the effect and mechanism of Lactobacillus casei Zhang in protecting against T2DM onset. Hyperglycemia was favorably suppressed by L. casei Zhang treatment. Moreover, the hyperglycemia was connected with type 1 immune response, high plasma bile acids and urine chloride ion loss. This chloride ion loss was significantly prevented by L. casei via upregulating of chloride ion-dependent genes (ClC1-7, GlyRα1, SLC26A3, SLC26A6, GABAAα1, Bestrophin-3 and CFTR). A shift in the caecal microflora, particularly the reduction of bile acid 7α-dehydroxylating bacteria, and fecal bile acid profiles also occurred. These change coincided with organ chloride influx. Thus, we postulate that the prevention of T2DM onset by L. casei Zhang may be via a microbiota-based bile acid-chloride exchange mechanism.
PMCID: PMC4135721  PMID: 25133590
Human genetics  2013;132(7):735-743.
Humans express at least seven alcohol dehydrogenase (ADH) isoforms that are encoded by ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5) at chromosome 4. ADHs are key catabolic enzymes for retinol and ethanol. The functional ADH variants (mostly rare) have been implicated in alcoholism risk. In addition to catalyzing the oxidation of retinol and ethanol, ADHs may be involved in the metabolic pathways of several neurotransmitters that are implicated in the neurobiology of neuropsychiatric disorders. In the present study, we comprehensively examined the associations between common ADH variants [minor allele frequency (MAF) >0.05] and 11 neuropsychiatric and neurological disorders. A total of 50,063 subjects in 25 independent cohorts were analyzed. The entire ADH gene cluster was imputed across these 25 cohorts using the same reference panels. Association analyses were conducted, adjusting for multiple comparisons. We found 28 and 15 single nucleotide polymorphisms (SNPs), respectively, that were significantly associated with schizophrenia in African-Americans and autism in European-Americans after correction by false discovery rate (FDR) (q <0.05); and 19 and 6 SNPs, respectively, that were significantly associated with these two disorders after region-wide correction by SNPSpD (8.9 × 10−5 ≤ p ≤ 0.0003 and 2.4 × 10−5 ≤ p ≤ 0.0003, respectively). No variants were significantly associated with the other nine neuropsychiatric disorders, including alcohol dependence. We concluded that common ADH variants conferred risk for both schizophrenia in African-Americans and autism in European-Americans.
PMCID: PMC3683370  PMID: 23468174
Statistica Sinica  2013;23(4):1553-1572.
Let Y1, …, Yn be a sequence whose underlying mean is a step function with an unknown number of the steps and unknown change points. The detection of the change points, namely the positions where the mean changes, is an important problem in such fields as engineering, economics, climatology and bioscience. This problem has attracted a lot of attention in statistics, and a variety of solutions have been proposed and implemented. However, there is scant literature on the theoretical properties of those algorithms. Here, we investigate a recently developed algorithm called the Screening and Ranking Algorithm (SaRa). We characterize the theoretical properties of SaRa and show its superiority over other commonly used algorithms. In particular, we develop a false discovery rate approach to the multiple change-point problem and show a strong sure coverage property for the SaRa.
PMCID: PMC3902887  PMID: 24489450
Change-point detection; copy number variation; false discovery rate; high dimensional data; screening and ranking algorithm
Pediatric research  2013;75(0):241-250.
Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd – 33rd week post-conception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory and vascular pathways, and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review.
Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH suggesting an as yet unknown environmental trigger. The methylenetetra-hydrofolate reeducates (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5 minute Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1 (COL4A1), a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role.
PMCID: PMC3946468  PMID: 24192699
BMC Microbiology  2014;14:150.
Economically, Leuconostoc lactis is one of the most important species in the genus Leuconostoc. It plays an important role in the food industry including the production of dextrans and bacteriocins. Currently, traditional molecular typing approaches for characterisation of this species at the isolate level are either unavailable or are not sufficiently reliable for practical use. Multilocus sequence typing (MLST) is a robust and reliable method for characterising bacterial and fungal species at the molecular level. In this study, a novel MLST protocol was developed for 50 L. lactis isolates from Mongolia and China.
Sequences from eight targeted genes (groEL, carB, recA, pheS, murC, pyrG, rpoB and uvrC) were obtained. Sequence analysis indicated 20 different sequence types (STs), with 13 of them being represented by a single isolate. Phylogenetic analysis based on the sequences of eight MLST loci indicated that the isolates belonged to two major groups, A (34 isolates) and B (16 isolates). Linkage disequilibrium analyses indicated that recombination occurred at a low frequency in L. lactis, indicating a clonal population structure. Split-decomposition analysis indicated that intraspecies recombination played a role in generating genotypic diversity amongst isolates.
Our results indicated that MLST is a valuable tool for typing L. lactis isolates that can be used for further monitoring of evolutionary changes and population genetics.
PMCID: PMC4063691  PMID: 24912963
Scientific Reports  2014;4:5001.
Historically, the Mongol Empire ranks among the world's largest contiguous empires, and the Mongolians developed their unique lifestyle and diet over thousands of years. In this study, the intestinal microbiota of Mongolians residing in Ulan Bator, TUW province and the Khentii pasturing area were studied using 454 pyrosequencing and q-PCR technology. We explored the impacts of lifestyle and seasonal dietary changes on the Mongolians' gut microbes. At the phylum level, the Mongolians's gut populations were marked by a dominance of Bacteroidetes (55.56%) and a low Firmicutes to Bacteroidetes ratio (0.71). Analysis based on the operational taxonomic unit (OTU) level revealed that the Mongolian core intestinal microbiota comprised the genera Prevotella, Bacteroides, Faecalibacterium, Ruminococcus, Subdoligranulum and Coprococcus. Urbanisation and life-style may have modified the compositions of the gut microbiota of Mongolians from Ulan Bator, TUW and Khentii. Based on a food frequency questionnaire, we found that the dietary structure was diverse and stable throughout the year in Ulan Bator and TUW, but was simple and varied during the year in Khentii. Accordingly, seasonal effects on intestinal microbiota were more distinct in Khentii residents than in TUW or Ulan Bator residents.
PMCID: PMC4023135  PMID: 24833488
Obstetrics and gynecology  2012;119(5):902-908.
To estimate whether progestin-induced endometrial shedding, prior to ovulation induction with clomiphene citrate, metformin, or a combination of both, affects ovulation, conception, and live birth rates in women with polycystic ovary syndrome (PCOS).
A secondary analysis of the data from 626 women with PCOS from the National Institutes of Child Health and Human Development Cooperative Reproductive Medicine Network trial was performed. Women had been randomized to up to six cycles of clomiphene citrate alone, metformin alone, or clomiphene citrate plus metformin. Women were assessed for occurrence of ovulation, conception, and live birth in relation to prior bleeding episodes (after either ovulation or exogenous progestin-induced withdrawal bleed).
While ovulation rates were higher in cycles preceded by spontaneous endometrial shedding than after anovulatory cycles (with or without prior progestin withdrawal), both conception and live birth rates were significantly higher after anovulatory cycles without progestin-induced withdrawal bleeding (live birth per cycle: spontaneous menses 2.2%; anovulatory with progestin withdrawal 1.6%; anovulatory without progestin withdrawal 5.3%; p<0.001). The difference was more marked when rate was calculated per ovulation (live birth per ovulation: spontaneous menses 3.0%; anovulatory with progestin withdrawal 5.4%; anovulatory without progestin withdrawal 19.7%; p < .001).
Conception and live birth rates are lower in women with PCOS after a spontaneous menses or progestin-induced withdrawal bleeding as compared to anovulatory cycles without progestin withdrawal. The common clinical practice of inducing endometrial shedding with progestin prior to ovarian stimulation may have an adverse effect on rates of conception and live birth in anovulatory women with PCOS.
PMCID: PMC4007263  PMID: 22525900
Trials  2014;15:154.
Polycystic ovary syndrome (PCOS) patients are at increased risk of pregnancy complications, which may impair pregnancy outcome. Transfer of fresh embryos after superovulation may lead to abnormal implantation and placentation and further increase risk for pregnancy loss and complications. Some preliminary data suggest that elective embryo cryopreservation followed by frozen–thawed embryo transfer into a hormonally primed endometrium could result in a higher clinical pregnancy rate than that achieved by fresh embryo transfer.
This study is a multicenter, prospective, randomized controlled clinical trial (1:1 treatment ratio of fresh vs. elective frozen embryo transfers).. A total of 1,180 infertile PCOS patients undergoing the first cycle of in vitro fertilization (IVF) or intracytoplasmic sperm injection will be enrolled and randomized into two parallel groups. Participants in group A will undergo fresh embryo transfer on day 3 after oocyte retrieval, and participants in group B will undergo elective embryo cryopreservation after oocyte retrieval and frozen–thawed embryo transfer in programmed cycles. The primary outcome is the live birth rate. Our study is powered at 80 to detect an absolute difference of 10 at the significance level of 0.01 based on a two-sided test.
We hypothesize that elective embryo cryopreservation and frozen–thawed embryo transfer will reduce the incidence of pregnancy complications and increase the live birth rate in PCOS patients who need IVF to achieve pregnancy.
Trial registration Identifier: NCT01841528
PMCID: PMC4022358  PMID: 24885793
Frozen–thawed embryo transfer; In vitro fertilization; Live birth; Polycystic ovarian syndrome
Drug and alcohol dependence  2013;129(3):254-264.
We aimed to identify novel, functional, replicable and genome-wide significant risk regions specific for alcohol dependence using genome-wide association studies (GWASs).
A discovery sample (1,409 European-American cases with alcohol dependence and 1,518 European-American controls) and a replication sample (6,438 European-Australian family subjects with 1,645 alcohol dependent probands) underwent association analysis. Nineteen other cohorts with 11 different neuropsychiatric disorders served as contrast groups. Additional eight samples underwent expression quantitative locus (eQTL) analysis.
A genome-wide significant risk gene region (NKAIN1-SERINC2) was identified in a meta-analysis of the discovery and replication samples. This region was enriched with 74 risk SNPs (unimputed); half of them had significant cis-acting regulatory effects. The distributions of -log(p) values for the SNP-disease associations or SNP-expression associations in this region were consistent throughout eight independent samples. Furthermore, imputing across the NKAIN1-SERINC2 region, we found that among all 795 SNPs in the discovery sample, 471 SNPs were nominally associated with alcohol dependence (1.7×10−7≤p≤0.047); 53 survived region- and cohort-wide correction for multiple testing; 92 SNPs were replicated in the replication sample (0.002≤p≤0.050). This region was neither significantly associated with alcohol dependence in African-Americans, nor with other non-alcoholism diseases. Finally, transcript expression of genes in NKAIN1-SERINC2 was significantly (p<3.4×10−7) associated with expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with alcohol dependence.
NKAIN1-SERINC2 may harbor a causal variant(s) for alcohol dependence. It may contribute to the disease risk by way of neurotransmitter systems or metabolic pathways.
PMCID: PMC3628730  PMID: 23455491
GWAS; genome-wide association studies; alcohol dependence; eQTL; risk region; replication
Alcohol and nicotine co-dependence can be considered as a more severe subtype of alcohol dependence. A portion of its risk may be attributable to genetic factors.
We searched for significant risk genomic regions specific for this disorder using a genome-wide association study (GWAS). A total of 8,847 subjects underwent gene-disease association analysis, including (i) a discovery cohort of 818 European-American cases with alcohol and nicotine co-dependence and 1,396 European-American controls, (ii) a replication cohort of 5,704 Australian family subjects with 907 affected offspring, and (iii) a replication cohort of 449 African-American cases and 480 African-American controls. Additionally, a total of 38,714 subjects of European or African descent in 18 independent cohorts with 10 other non-alcoholism neuropsychiatric disorders were analyzed as contrast. Furthermore, 90 unrelated HapMap CEU individuals, 93 European brain tissue samples and 80 European peripheral blood mononuclear cell (PBMC) samples underwent cis-acting expression quantitative locus (cis-eQTL) analysis.
We identified a significant risk region for alcohol and nicotine co-dependence between IPO11 and HTR1A on chromosome 5q that was reported to be suggestively associated with alcohol dependence previously. In the European-American discovery cohort, 381 SNPs in this region were nominally associated with alcohol and nicotine co-dependence (p<0.05); 57 associations of them survived region- and cohort-wide correction (α=3.6×10−6); and the top SNP (rs7445832) was significantly associated with alcohol and nicotine co-dependence at the genome-wide significance level (p=6.2×10−9). Furthermore, associations for 34 and 11 SNPs were replicated in the Australian and African-American replication cohorts, respectively. Among these replicable associations, 4 reached genome-wide significance level in the meta-analysis of European-Americans and European-Australians: rs7445832 (p=9.6×10−10), rs13361996 (p=8.2×10−9), rs62380518 (p=2.3×10−8) and rs7714850 (p=3.4×10−8). Cis-eQTL analysis showed that many risk SNPs in this region had nominally significant cis-acting regulatory effects on HTR1A or IPO11 mRNA expression. Finally, no markers were significantly associated with any other neuropsychiatric disorder examined.
We speculate that this IPO11-HTR1A region might harbor a causal variant for alcohol and nicotine co-dependence.
PMCID: PMC3610804  PMID: 23216389
GWAS; alcohol and nicotine co-dependence; cis-eQTL; IPO11; HTR1A
PLoS ONE  2014;9(4):e93631.
The human gut microbiota consists of complex microbial communities, which possibly play crucial roles in physiological functioning and health maintenance. China has evolved into a multicultural society consisting of the major ethnic group, Han, and 55 official ethnic minority groups. Nowadays, these minority groups inhabit in different Chinese provinces and some of them still keep their unique culture and lifestyle. Currently, only limited data are available on the gut microbiota of these Chinese ethnic groups. In this study, 10 major fecal bacterial groups of 314 healthy individuals from 7 Chinese ethnic origins were enumerated by quantitative polymerase chain reaction. Our data confirmed that the selected bacterial groups were common to all 7 surveyed ethnicities, but the amount of the individual bacterial groups varied to different degree. By principal component and canonical variate analyses of the 314 individuals or the 91 Han subjects, no distinct group clustering pattern was observed. Nevertheless, weak differences were noted between the Han and Zhuang from other ethnic minority groups, and between the Heilongjiang Hans from those of the other provinces. Thus, our results suggest that the ethnic origin may contribute to shaping the human gut microbiota.
PMCID: PMC3974763  PMID: 24699404
The Journal of pediatrics  2012;162(4):713-718.e2.
To investigate whether prenatal exposure to nicotine has an impact on several reading skill outcomes in school age children.
Study design
Using a longitudinal sample of 5,119 school age children in the Avon Longitudinal Study of Parents and Children (ALSPAC), this study investigated specific reading skill outcomes in the area of speed, fluency, accuracy, spelling and comprehension in relation to prenatal nicotine exposure, after adjusting for potential mediators and confounders. Prenatal nicotine exposure was divided into three categories: high (>17mg per day), low (≤17mg per day) and no exposure.
We found that prenatal nicotine exposure was associated with increased risk of underperformance in specific reading skill outcomes after adjusting for potential mediators and confounders (p = .006). The effect of poor performance in decoding single words was most pronounced among children with prenatal exposure to high levels of nicotine in conjunction with a phonological deficit. Overall the results showed that maternal smoking has moderate to large associations with delayed or decreased reading skills of children in the ALSPAC.
High prenatal nicotine exposure has a negative association with reading performance in school age children. In addition, modeling showed that environmental factors significantly moderated the interaction between prenatal nicotine exposure and reading skill outcomes.
PMCID: PMC3577994  PMID: 23122624
Reading performance; reading skills; prenatal exposure to nicotine; ALSPAC

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