Xingbin Wang

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Papers by Xingbin Wang

Resequencing of the CETP gene in American whites and African blacks: Association of rare and common variants with HDL-cholesterol levels

Metabolism, 2015

Cholesteryl ester transfer protein (CETP) plays a crucial role in lipid metabolism. Associations ... more Cholesteryl ester transfer protein (CETP) plays a crucial role in lipid metabolism. Associations of common CETP variants with variation in plasma lipid levels, and/or CETP mass/activity have been extensively studied and well-documented; however, the effects of uncommon/rare CETP variants on plasma lipid profile remain undefined. Hence, resequencing of the gene in extreme phenotypes and follow-up rare-variant association analyses are essential to fill this gap. To identify common and uncommon/rare variants in the CETP gene by resequencing the entire gene and test the effects of both common and uncommon/rare CETP variants on plasma lipid traits in two genetically distinct populations. The entire CETP gene plus flanking regions were resequenced in 190 individuals comprising 95 non-Hispanic whites (NHWs) and 95 African blacks with extreme HDL-C levels. A total of 279 sequence variants were identified, of which 25 were novel. Selected variants were genotyped in the entire samples of 623 NHWs and 788 African blacks and 184 QC-passed variants were tested in relation to plasma lipid traits by using gene-based, single-site, haplotype and rare variant association analyses (SKAT-O). Two novel and independent associations of rs1968905 and rs289740 with HDL-C were identified in African blacks. Using SKAT-O analysis, we also identified rare variants with minor allele frequency &lt;0.01 to be associated with HDL-C in both NHWs (P=0.024) and African blacks (P=0.009). Our results point out that in addition to the common CETP variants, rare genetic variants in the CETP gene also contribute to the phenotypic variation of HDL-C in the general population.

Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry

Arthritis & rheumatology (Hoboken, N.J.), Jan 28, 2015

Genome-wide association studies (GWASs) in individuals of European ancestry identified a number o... more Genome-wide association studies (GWASs) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Follow-up studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in European-descent subjects. Here we report the results of a multi-stage study that we performed to identify novel SLE loci. In Stage 1, we conducted a new GWAS of SLE in a North American case-control sample of European ancestry (n=1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In Stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional dataset of European-descent subjects (>2,500 individuals), followed by replication of top meta-analysis findings in another dataset of European-descent subjects (>10,000 individuals) in Stage 3. As expected, our GWAS revealed most signifi...

Plasma and cerebrospinal fluid alpha-1-antichymotrypsin levels in Alzheimer's disease: correlation with cognitive impairment

alpha-1-Antichymotrypsin (ACT) is present in neuritic plaques in which it participates in the inf... more alpha-1-Antichymotrypsin (ACT) is present in neuritic plaques in which it participates in the inflammatory cascade of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). Reports of blood ACT levels in AD, and its usefulness as a disease biomarker, have been conflicting. In an effort to clarify this, we measured plasma ACT levels in 516 white subjects including 359 subjects with probable or possible AD, 44 subjects with other late-life dementias, and 113 nondemented people. Subjects with systemic inflammatory diseases or who were taking antiinflammatory medications were excluded. All patients underwent extensive medical and detailed neuropsychological examinations at the time their blood was drawn. We found that plasma ACT levels were elevated in AD patients compared with the control group (p = 0.01) and were associated with severity of AD dementia; there was a negative association with the Mattis Dementia Rating Scale (a global measure of cognition) and a positive association with the Clinical Dementia Rating Scale (a global functional assessment). These relationships remained significant after controlling for demographic and genetic variables. When AD subjects were stratified into subgroups by dementia severity, matched by age, education, and gender, increased serum ACT correlated with Clinical Dementia Rating Scale (p = 0.0041) or Mattis Dementia Rating Scale (p = 0.0031) scores. ACT measurements in cerebrospinal fluid from an additional 34 AD cases and 16 controls showed elevated levels (p = 0.02) in AD. There was a negative correlation (p = 0.037) between cerebrospinal fluid ACT levels and clinical severity as measured by the Mini-Mental State Examination. Our results demonstrate that peripheral ACT levels are elevated in AD, but not in dementias other than AD, and they increase with progression of AD dementia. Although not useful as a diagnostic biomarker, ACT may reflect disease severity and may be helpful as a within subject biomarker in interventions (particularly with antiinflammatory agents) directed at slowing or halting progression of disease.

Relation Between Dental Fear and Fear of Pain: How Heritable?

Objectives: Though individual behavior undoubtedly is influenced by environment and learning hist... more Objectives: Though individual behavior undoubtedly is influenced by environment and learning history (i.e., previous experiences), understanding the role of genetics in the etiologies and prognoses of dental fear and anxiety is an important step toward a full conceptualization of these psychosocial barriers to dental treatment. Dental fear previously has been shown to be heritable; however, no study has addressed the heritability of fear of pain, a central component of dental fear. The current project aimed to improve our understanding of the influence of genes on dental fear by addressing the heritability of fear of pain. Methods: Participants (n = 1371; 632 female), ages 11 – 81 years (M = 29.1, SD = 12.2), completed the Dental Fear Survey and the Fear of Pain Questionnaire – Short Form. These individuals were members of families taking part in the protocol for the Center for Oral Health Research in Appalachia study on determinants of oral diseases in families. Heritability and ge...

More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer’s disease risk

Neurobiology of Aging, 2015

Over 20 risk loci have been identified for late-onset Alzheimer&amp;amp;amp;amp;amp;amp;amp;a... more Over 20 risk loci have been identified for late-onset Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here, we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (odds ratio = 7.40, p = 3.66E-06). In addition to Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease risk, we also examined the association of R47H with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease-related phenotypes, including age-at-onset, psychosis, and amyloid deposition but found no significant association. Our results corroborate those of other studies implicating TREM2 as an LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration.

Genetic Determinants of Survival in Patients with Alzheimer's Disease

Journal of Alzheimer's disease : JAD, Jan 3, 2015

There is a strong genetic basis for late-onset of Alzheimer's disease (LOAD), and thus far &g... more There is a strong genetic basis for late-onset of Alzheimer's disease (LOAD), and thus far >20 genes/loci have been identified that affect the risk of LOAD. In addition to disease risk, genetic variation at these loci may also affect components of the natural history of AD, such as survival in AD. In this study, we first examined the role of known LOAD genes with survival time in 983 AD patients. We then performed genome-wide single-nucleotide polymorphism (SNP) and gene-based association analyses to identify novel loci that may influence survival of AD. Survival analysis was conducted using Cox proportional hazards regression under an additive genetics model. We found multiple nominally significant associations (p < 0.01) either within or adjacent to known LOAD genes. Genome-wide SNP analysis identified multiple suggestive novel loci and two of them were also significant in gene-based analysis (CCDC85C and NARS2) that survived after controlling for false-discovery rate at...

Comprehensive Evaluation of the Association of APOE Genetic Variation with Plasma Lipoprotein Traits in U.S. Whites and African Blacks

PLoS ONE, 2014

Although common APOE genetic variation has a major influence on plasma LDL-cholesterol, its role ... more Although common APOE genetic variation has a major influence on plasma LDL-cholesterol, its role in affecting HDL-cholesterol and triglycerides is not well established. Recent genome-wide association studies suggest that APOE also affects plasma variation in HDL-cholesterol and triglycerides. It is thus important to resequence the APOE gene to identify both common and uncommon variants that affect plasma lipid profile. Here, we have sequenced the APOE gene in 190 subjects with extreme HDL-cholesterol levels selected from two well-defined epidemiological samples of U.S. non-Hispanic Whites (NHWs) and African Blacks followed by genotyping of identified variants in the entire datasets (623 NHWs, 788 African Blacks) and association analyses with major lipid traits. We identified a total of 40 sequence variants, of which 10 are novel. A total of 32 variants, including common tagSNPs (≥5% frequency) and all uncommon variants (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;5% frequency) were successfully genotyped and considered for genotype-phenotype associations. Other than the established associations of APOE*2 and APOE*4 with LDL-cholesterol, we have identified additional independent associations with LDL-cholesterol. We have also identified multiple associations of uncommon and common APOE variants with HDL-cholesterol and triglycerides. Our comprehensive sequencing and genotype-phenotype analyses indicate that APOE genetic variation impacts HDL-cholesterol and triglycerides in addition to affecting LDL-cholesterol.

Resequencing of LPL in African Blacks and associations with lipoprotein–lipid levels

European Journal of Human Genetics, 2015

Genome-wide association studies have identified several loci associated with plasma lipid levels ... more Genome-wide association studies have identified several loci associated with plasma lipid levels but those common variants together account only for a small proportion of the genetic variance of lipid traits. It has been hypothesized that the remaining heritability may partly be explained by rare variants with strong effect sizes. Here, we have comprehensively investigated the associations of both common and uncommon/rare variants in the lipoprotein lipase (LPL) gene in relation to plasma lipoproteinlipid levels in African Blacks (ABs). For variant discovery purposes, the entire LPL gene and flanking regions were resequenced in 95 ABs with extreme high-density lipoprotein cholesterol (HDL-C) levels. A total of 308 variants were identified, of which 64 were novel. Selected common tagSNPs and uncommon/rare variants were genotyped in the entire sample (n = 788), and 126 QC-passed variants were evaluated for their associations with lipoprotein-lipid levels by using single-site, haplotype and rare variant (SKAT-O) association analyses. We found eight not highly correlated (r 2 o0.40) signals (rs1801177:G4A, rs8176337: G4C, rs74304285:G4A, rs252:delA, rs316:C4A, rs329:A4G, rs12679834:T4C, and rs4921684:C4T) nominally (Po0.05) associated with lipid traits (HDL-C, LDL-C, ApoA1 or ApoB levels) in our sample. The most significant SNP, rs252:delA, represented a novel association observed with LDL-C (P = 0.002) and ApoB (P = 0.012). For TG and LDL-C, the haplotype analysis was more informative than the single-site analysis. The SKAT-O analysis revealed that the bin (group) containing 22 rare variants with MAF ≤ 0.01 exhibited nominal association with TG (P = 0.039) and LDL-C (P = 0.027). Our study indicates that both common and uncommon/rare LPL variants/haplotypes may affect plasma lipoprotein-lipid levels in general African population.

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The Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes Across Species

Frontiers in Psychiatry, 2013

Although circulating hormones and inhibitory gamma-aminobutyric acid (GABA)-related factors are k... more Although circulating hormones and inhibitory gamma-aminobutyric acid (GABA)-related factors are known to affect mood, considerable knowledge gaps persist for biological mechanisms underlying the female bias in mood disorders. Here, we combine human and mouse studies to investigate sexual dimorphism in the GABA system in the context of major depressive disorder (MDD) and then use a genetic model to dissect the role of sex-related factors in GABA-related gene expression and anxiety-/depressive-like behaviors in mice. First, using meta-analysis of gene array data in human postmortem brain (N = 51 MDD subjects, 50 controls), we show that the previously reported down-regulation in MDD of somatostatin (SST ), a marker of a GABA neuron subtype, is significantly greater in women with MDD. Second, using gene co-expression network analysis in control human subjects (N = 214; two frontal cortex regions) and expression quantitative trait loci mapping (N = 170 subjects), we show that expression of SST and the GABA-synthesizing enzymes glutamate decarboxylase 67 (GAD67 ) and GAD65 are tightly co-regulated and influenced by X-chromosome genetic polymorphisms. Third, using a rodent genetic model [Four Core Genotypes (FCG) mice], in which genetic and gonadal sex are artificially dissociated (N ≥ 12/group), we show that genetic sex (i.e., X/Y-chromosome) influences both gene expression (lower Sst, Gad67, Gad65 in XY mice) and anxiety-like behaviors (higher in XY mice). This suggests that in an intact male animal, the observed behavior represents the outcomes of male genetic sex increasing and male-like testosterone decreasing anxiety-like behaviors. Gonadal sex was the only factor influencing depressive-like behavior (gonadal males < gonadal females). Collectively, these combined human and mouse studies provide mechanistic insight into sexual dimorphism in mood disorders, and specifically demonstrate an unexpected role of male-like factors (XY genetic sex) on GABA-related genes and anxiety-like behaviors.

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Genome-wide association study of antiphospholipid antibodies

Autoimmune Diseases, 2013

Background. The persistent presence of antiphospholipid antibodies (APA) may lead to the developm... more Background. The persistent presence of antiphospholipid antibodies (APA) may lead to the development of primary or secondary antiphospholipid syndrome. Although the genetic basis of APA has been suggested, the identity of the underlying genes is largely unknown. In this study, we have performed a genome-wide association study (GWAS) in an effort to identify susceptibility loci/genes for three main APA: anticardiolipin antibodies (ACL), lupus anticoagulant (LAC), and anti-2 glycoprotein I antibodies (anti-2 GPI). Methods. DNA samples were genotyped using the Affymetrix 6.0 array containing 906,600 single-nucleotide polymorphisms (SNPs). Association of SNPs with the antibody status (positive/negative) was tested using logistic regression under the additive model. Results. We have identified a number of suggestive novel loci with < − 05. Although they do not meet the conservative threshold of genome-wide significance, many of the suggestive loci are potential candidates for the production of APA. We have replicated the previously reported associations of HLA genes and APOH with APA but these were not the top loci. Conclusions. We have identified a number of suggestive novel loci for APA that will stimulate follow-up studies in independent and larger samples to replicate our findings.

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Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

British Journal of Cancer, 2012

Association of PHB 1630 C4T and MTHFR 677 C4T polymorphisms with breast and ovarian cancer risk i... more Association of PHB 1630 C4T and MTHFR 677 C4T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C4T (rs6917) polymorphism and the MTHFR 677 C4T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C4T and MTHFR 677 C4T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C4T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

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Molecular and Genetic Characterization of Depression: Overlap with Other Psychiatric Disorders and Aging

Molecular Neuropsychiatry, 2015

suggest altered neurotrophic support, brain plasticity and neuronal signaling in MDD. Notably, me... more suggest altered neurotrophic support, brain plasticity and neuronal signaling in MDD. Notably, metaA-MDD genes display a low connectivity and hubness in coexpression networks as well as a uniform genomic distribution, which is consistent with diffuse polygenic mechanisms. We have integrated these findings with results from over 1,800 published GWAS and show that genetic variations nearby metaA-MDD genes predict a greater risk for neuropsychiatric disorders, and notably for age-related phenotypes, but not for other medical illnesses (including those frequently co-occurring with depression) or body characteristics. Collectively, the intersection of unbiased investigations of gene function (transcriptome) and structure (GWAS) provides novel leads to investigate molecular mechanisms of MDD and suggests common biological pathways between depression, other neuropsychiatric diseases and brain aging.

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Beta-amyloid toxicity modifier genes and the risk of Alzheimer's disease

American journal of neurodegenerative disease, 2012

Late-onset Alzheimer's disease (LOAD) is a complex and multifactorial disease. So far ten loc... more Late-onset Alzheimer's disease (LOAD) is a complex and multifactorial disease. So far ten loci have been identified for LOAD, including APOE, PICALM, CLU, BIN1, CD2AP, CR1, CD33, EPHA1, ABCA7, and MS4A4A/MS4A6E, but they explain about 50% of the genetic risk and thus additional risk genes need to be identified. Amyloid beta (Aβ) plaques develop in the brains of LOAD patients and are considered to be a pathological hallmark of this disease. Recently 12 new Aβ toxicity modifier genes (ADSSL1, PICALM, SH3KBP1, XRN1, SNX8, PPP2R5C, FBXL2, MAP2K4, SYNJ1, RABGEF1, POMT2, and XPO1) have been identified that potentially play a role in LOAD risk. In this study, we have examined the association of 222 SNPs in these 12 candidate genes with LOAD risk in 1291 LOAD cases and 958 cognitively normal controls. Single site and haplotype analyses were performed using PLINK. Following adjustment for APOE genotype, age, sex, and principal components, we found single nucleotide polymorphisms (SNPs) i...

Genetic determinants of disease progression in Alzheimer's disease

Journal of Alzheimer's disease : JAD, 2015

There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/... more There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer's Disease Research Center. Patients were classified as "rapid progressors" if the Mini-Mental State Examination (MMSE) changed ≥3 points in 12 months and "slow progressors" if the MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between single nucleotide polymorphisms (SNPs) and the progression status of the AD cases was performed using logistic regression model controlled for age, gender,...

Genetic Variation in Imprinted Genes is Associated with Risk of Late-Onset Alzheimer's Disease

Journal of Alzheimer's disease : JAD, Jan 12, 2014

Epigenetic changes including genomic imprinting may affect risk of late-onset Alzheimer's dis... more Epigenetic changes including genomic imprinting may affect risk of late-onset Alzheimer's disease (LOAD). There are >100 known imprinted genes and most of them are expressed in human brain. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in 93 imprinted genes with LOAD risk in 1291 LOAD cases and 958 cognitively normal controls. We performed single-site, gene-based, and haplotype analyses. Single-site analysis showed 14 significant associations at p < 0.01. The most significant SNP (rs11770199; p = 0.0003) in single-site analysis was located on chromosome 7 in the GRB10 gene. Gene-based analyses revealed four significant associations in the WT1, ZC3H12C, DLGAP2, and GPR1 genes at p < 0.05. The haplotype analysis also revealed significant associations with three genes (ZC3H12C, DLGAP2, and GPR1). These findings suggest a possible role of imprinted genes in AD pathogenesis that show specific expression in the brain.

Genetic Susceptibility to Dental Caries Differs between the Sexes: A Family-Based Study

Caries Research, 2015