Tao Li

A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn)

Haplotypic information in diploid organisms provides valuable information on human evolutionary history and plays an important role in identifying a candidate gene in the etiology of complex genetic diseases. However, haplotypes of diploid individuals cannot be acquired easily. Molecular haplotyping methods are very costly and have low throughput, and current genotyping and sequencing methods do not provide information on the linkage phase in diploid organisms. The application of statistical methods to infer the haplotype phase in samples of diploid sequences is a very cost-effective approach. Several computational and statistical methods have been developed for haplotype inference, including Clark’s algorithm [1], the Expectation Maximization (EM) algorithm [2], and Gibbs sampler [3]. Because of its interpretability and stability, the EM algorithm has become one of the most widely used statistical algorithms. However, the standard EM algorithm has several weaknesses, including the inability to handle a large number of markers and convergence to the local optimum. To overcome these problems, various derivative methods have been developed, such as the Partition-Ligation EM (PLEM) algorithm to handle many more linked loci [4], the Optimal Step Length EM (OSLEM) algorithm to accelerate the calculations [5], and the Stochastic EM (SEM) algorithm to deal with missing genotypic data and to avoid convergence to local maxima [6]. However, most packages are intended for use with single-nucleotide polymorphism (SNP) data in a biallelic manner. More and more researchers are analyzing both multiallelic and biallelic markers in the linkage and/or association studies of complex diseases. The analysis of linkage disequilibrium (LD) between multiallelic loci and haplotype inference of many loci (including biand multiallelic markers) present a number of common problems. The major difficulty for the haplotype inference problem npg Cell Research (2009) 19:519-523.

Common variants on 8p12 and 1q24.2 confer risk of schizophrenia

Schizophrenia is a severe mental disorder affecting ∼1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10−10) and 1q24.2 (rs10489202, P = 9.50 × 10−9). Our findings provide new insights into the pathogenesis of schizophrenia.

Sirtuin 1–Mediated Cellular Metabolic Memory of High Glucose Via the LKB1/AMPK/ROS Pathway and Therapeutic Effects of Metformin

Cellular metabolic memory occurs in diabetic microvascular and macrovascular complications, but the underlying mechanisms remain unclear. Here, we investigate the role of sirtuin 1 (SIRT1) and metformin in this phenomenon. In bovine retinal capillary endothelial cells (BRECs) and retinas of diabetic rats, the inflammatory gene, nuclear factor-κB (NF-κB), and the proapoptotic gene, Bax, induced by hyperglycemia, remained elevated after returning to normoglycemia. BRECs with small interfering RNA–mediated SIRT1 knockdown had increased sensitivity to hyperglycemia stress, whereas SIRT1 overexpression or activation by metformin inhibited the increase of mitochondrial reactive oxygen species–mediated glyceraldehyde-3-phosphate dehydrogenase by poly (ADP-ribose) polymerase (PARP) activity through the upregulation of liver kinase B1/AMP-activated protein kinase (LKB1/AMPK), ultimately suppressing NF-κB and Bax expression. Furthermore, we showed that hyperglycemia led to PARP activation, which in turn may have downregulated SIRT1. Of importance, this study also demonstrated that metformin suppressed the “memory” of hyperglycemia stress in the diabetic retinas, which may be involved in the SIRT1/LKB1/AMPK pathway. Our data suggest that SIRT1 is a potential therapeutic target for the treatment of the cellular metabolic memory, and the use of metformin specifically for such therapy may be a new avenue of investigation in the diabetes field.

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma

Despite progress in the diagnostics and treatment of hepatocellular carcinoma (HCC), its prognosis remains poor. In this study, we globally assessed long noncoding RNAs (lncRNA) for contributions to HCC using publicly available microarray data, in vitro and in vivo assays. Here, we report that ZFAS1, encoding a lncRNA that is frequently amplified in HCC, is associated with intrahepatic and extrahepatic metastasis and poor prognosis of HCC. ZFAS1 functions as an oncogene in HCC progression by binding miR-150 and abrogating its tumor-suppressive function in this setting. miR-150 repressed HCC cell invasion by inhibiting ZEB1 and the matrix metalloproteinases MMP14 and MMP16. Conversely, ZFAS1 activated ZEB1, MMP14, and MMP16 expression, inhibiting these effects of miR-150. Our results establish a function for ZFAS1 in metastatic progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of HCC.

Common Variants in Major Histocompatibility Complex Region and TCF4 Gene Are Significantly Associated with Schizophrenia in Han Chinese

BACKGROUNDnSchizophrenia is a complex major psychiatric disorder affecting ∼1% of the world population. Recently, in a genome-wide association study and a follow-up in Caucasians, Stefansson et al. examined 7662 schizophrenic cases and 29053 normal control subjects and reported seven common single nucleotide polymorphisms (SNPs) that were significantly (>10(-8)) associated with schizophrenia.nnnMETHODSnTo investigate whether these risk SNPs were significantly associated in Han Chinese, we analyzed the seven SNPs in 2496 schizophrenia patients and 5184 normal control subjects. Because only three of the seven SNPs were polymorphic in Han Chinese, we genotyped two additional common SNPs from the same risk regions.nnnRESULTSnThree SNPs, rs6932590 (p = .00096), rs3131296 (p = 1.29 × 10(-6)), and rs3130375 (p = 1.76 × 10(-5)), mapping to the major histocompatibility complex region and one SNP rs2958182 (p = 3.64 × 10(-6)) located in the TCF4 gene were significant in our sample set. A meta-analysis using published genome-wide association study results also supported our findings.nnnCONCLUSIONSnOur results confirm that common risk factors in the major histocompatibility complex region and TCF4 gene are associated with schizophrenia in Han Chinese, but our results fail to show an association with SNP rs12807809 in the NRGN gene.

A genome-wide association study reveals association between common variants in an intergenic region of 4q25 and high-grade myopia in the Chinese Han population

High-grade myopia (HM) is highly heritable, and has a high prevalence in the Han Chinese population. We carried out a genome-wide association study involving 102 HM cases suffering from retinal degeneration, and 335 controls who were free from HM and fundus diseases. Significant single-nucleotide polymorphisms were replicated in two follow-up studies: stage I involved 2628 independent cases and 9485 controls, and stage II involved a further 263 cases and 586 HM-free controls. The results were combined in a meta-analysis. Cases and controls were drawn from the Chinese Han population. A locus in an intergenic region at 4q25, within MYP11 (4q22-q27, OMIM: 609994), was found to be associated with HM (rs10034228, P(meta) = 7.70 × 10(-13), allelic odds ratio = 0.81, 95% confidence interval 0.76-0.86). There are no known genes in the region but a number of expressed sequence tags (ESTs) have been located there, one of which (BI480957) has been reported to express in the native human retinal pigment epithelium. In addition, a predicted gene was identified in this region. The genes predicted protein sequence is highly similar to tubulin, beta 8 and beta-tubulin 4Q. Several previous studies have shown that tubulin plays an important role in eye development. Our result is compatible with a previous linkage study in the Han Chinese population (mapping in MYP11, 4q22-q27), and provides a more accurate locus for HM. Although there is insufficient evidence to indicate that expressed EST and the predicted gene play an important role in developing HM, this region merits further study as a candidate for the disease.

CACNA1C, schizophrenia and major depressive disorder in the Han Chinese population

BACKGROUNDnCommon psychiatric disorders are highly heritable, indicating that genetic factors play an important role in their aetiology. The CACNA1C gene, which codes for subunit alpha-1C of the Cav1.2 voltage-dependent L-type calcium channel, has been consistently found to be the shared risk gene for several kinds of mental disorder.nnnAIMSnTo investigate whether CACNA1C is a susceptibility gene for schizophrenia and major depressive disorder in the Han Chinese population.nnnMETHODnWe carried out a case-control study of 1235 patients with schizophrenia, 1045 with major depressive disorder and 1235 healthy controls. A tag single nucleotide polymorphism (SNP) rs1006737 along with another 10 tag SNPs in the CACNA1C gene were genotyped in all samples.nnnRESULTSnWe found that rs1006737 was associated with both schizophrenia (P(allele) = 0.0014, P(genotype) = 0.006, odds ratio (OR) = 1.384, 95% CI 1.134-1.690) and major depressive disorder (P(allele) = 0.0007, P(genotype) = 0.003, OR = 1.425, 95% CI 1.160-1.752).nnnCONCLUSIONSnOur findings support CACNA1C being a risk gene for both schizophrenia and major depressive disorder in the Han Chinese population.

Common variants in the BCL9 gene conferring risk of schizophrenia.

CONTEXTnRecent genome-wide association studies have revealed that common variations and rare copy-number variations contribute to the risk of mental disorders. Rare recurrent microdeletions at 1q21.1 were reported to be associated with schizophrenia, and the BCL9 gene at 1q21.1 was also a functional candidate gene for mental disorders.nnnOBJECTIVESnTo investigate and validate whether common variations exist in a functional candidate gene in the copy-number variation region, and, if so, to determine whether these variations confer risk of schizophrenia or other mental disorders.nnnDESIGNnA 3-stage case-control study.nnnSETTINGnShanghai, China.nnnPARTICIPANTSnA total of 12 229 subjects were included: 5772 normal controls, 4187 patients with schizophrenia, 1135 patients with bipolar disorder patients, and 1135 patients with major depressive disorder. Main Outcome Measure During the first and second stages of our study, we genotyped 10 single-nucleotide polymorphisms using the ligation detection reaction method. During the third stage of our study, all single-nucleotide polymorphisms were genotyped using TaqMan technology (Applied Biosystems, Foster City, California).nnnRESULTSnDuring the first stage of our study, we found that rs672607 was significantly associated with schizophrenia (P = 2.69 × 10(-5)). During the second stage, rs672607 was successfully replicated (P = 1.33 × 10(-5)), and rs9326555 (P = .002), rs1240083 (P = 1.7 × 10(-4)), and rs688325 (P = .006) were newly identified to be significant. During the third stage, we genotyped all single-nucleotide polymorphisms in 1135 patients with schizophrenia, 1135 patients with bipolar disorder, 1135 patients with major depressive disorder, and 1135 normal controls for further validation. Finally, when we combined all the data from the 3 stages of our schizophrenia study, we found that rs9326555 (P = 1.53 × 10(-5)), rs10494251 (P = .02), rs1240083 (P = 1.52 × 10(-4)), rs672607 (P = 1.23 × 10(-11)), rs688325 (P = 2.54 × 10(-4)), and rs3766512 (P = .01) were significant. Moreover, we found that rs672607 was significant in major depressive disorder (P = .001) and bipolar disorder (P = .03), and rs10494251 (P = .04), rs1541187 (P = .04), rs688325 (P = .02), and rs946903 (P = .006) were significant in major depressive disorder.nnnCONCLUSIONnThese findings indicate that common variations in the BCL9 gene confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder in the Chinese Han population.

Rare CNVs and Tag SNPs at 15q11.2 Are Associated With Schizophrenia in the Han Chinese Population

BACKGROUNDnRare copy number variations (CNVs) were involved in the etiology of neuropsychiatric disorders, and some of them appeared to be shared risk factors for several different diseases. One of those promising loci is the CNV at 15q11.2, including 4 genes, TUBGCP5, CYFIP1, NIPA2, and NIPA1. Several studies showed that microdeletions at this locus were significant associated with schizophrenia. In the current study, we investigated the role of both rare CNVs and common single nucleotide polymorphisms (SNPs) at 15q11.2 in schizophrenia in the Chinese Han population.nnnMETHODSnWe screened deletions at 15q11.2 in 2058 schizophrenia patients and 3275 normal controls in Chinese Han population by Affymetrix 500K/6.0 SNP arrays and SYBR green real-time polymerase chain reaction and then validated deletions by multiplex ligation-dependent probe amplification and Taqman real-time assays. We successfully genotyped 27 tag SNPs in total and tested associations in 1144 schizophrenia cases and 1144 normal controls.nnnRESULTSnWe found a triple increase of deletions in cases over controls, with OR=4.45 (95% CI=1.36-14.60) and P=.014. In the analysis of common SNPs, we found that the most significant SNP in schizophrenia was rs4778334 (OR=.72, 95% CI=0.60-0.87, allelic P=.0056 after permutation, genotypic P=.015 after permutation). We also found SNP rs1009153 in CYFIP1 was associated with schizophrenia (OR=0.82, 95% CI=0.73-0.93, allelic P=.044 after permutation).nnnCONCLUSIONnWe found that both rare deletions and common variants at 15q11.2 were associated with schizophrenia in the Chinese Han population.

CNTNAP2 is significantly associated with schizophrenia and major depression in the Han Chinese population.

CNTNAP2, located on 7q35-36.1, encodes a single-pass transmembrane protein mediating cell-cell interactions in the nervous system. CNTNAP2 has been suggested to play an important role in mental diseases such as autism and language disorder. However, we still do not know whether it also confers risk to major psychiatric disorders such as schizophrenia, major depression and bipolar disorder. We analysed single nucleotide polymorphisms (SNPs) previously reported to be associated with autism or language impairment in 1135 schizophrenia patients, 1135 unrelated major depression patients, 1135 unrelated bipolar disorder patients and 1135 unrelated normal controls recruited from the Han Chinese population. We found that the genotypes of rs17236239 were significantly associated with schizophrenia and the alleles of rs2710102 and rs2710117 were significantly associated with major depression. According to the location of significant signals, our study indicated that exon 13-15 of CNTNAP2 may play important roles in both schizophrenia and major depression in the Han Chinese population.