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author:("Liu, chungju")
1.  Pathway Analyses Implicate Glial Cells in Schizophrenia 
PLoS ONE  2014;9(2):e89441.
The quest to understand the neurobiology of schizophrenia and bipolar disorder is ongoing with multiple lines of evidence indicating abnormalities of glia, mitochondria, and glutamate in both disorders. Despite high heritability estimates of 81% for schizophrenia and 75% for bipolar disorder, compelling links between findings from neurobiological studies, and findings from large-scale genetic analyses, are only beginning to emerge.
Ten publically available gene sets (pathways) related to glia, mitochondria, and glutamate were tested for association to schizophrenia and bipolar disorder using MAGENTA as the primary analysis method. To determine the robustness of associations, secondary analyses were performed with: ALIGATOR, INRICH, and Set Screen. Data from the Psychiatric Genomics Consortium (PGC) were used for all analyses. There were 1,068,286 SNP-level p-values for schizophrenia (9,394 cases/12,462 controls), and 2,088,878 SNP-level p-values for bipolar disorder (7,481 cases/9,250 controls).
The Glia-Oligodendrocyte pathway was associated with schizophrenia, after correction for multiple tests, according to primary analysis (MAGENTA p = 0.0005, 75% requirement for individual gene significance) and also achieved nominal levels of significance with INRICH (p = 0.0057) and ALIGATOR (p = 0.022). For bipolar disorder, Set Screen yielded nominally and method-wide significant associations to all three glial pathways, with strongest association to the Glia-Astrocyte pathway (p = 0.002).
Consistent with findings of white matter abnormalities in schizophrenia by other methods of study, the Glia-Oligodendrocyte pathway was associated with schizophrenia in our genomic study. These findings suggest that the abnormalities of myelination observed in schizophrenia are at least in part due to inherited factors, contrasted with the alternative of purely environmental causes (e.g. medication effects or lifestyle). While not the primary purpose of our study, our results also highlight the consequential nature of alternative choices regarding pathway analysis, in that results varied somewhat across methods, despite application to identical datasets and pathways.
PMCID: PMC3933626  PMID: 24586781
2.  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.
PMCID: PMC3905728  PMID: 24253340
3.  Predicting Active Users' Personality Based on Micro-Blogging Behaviors 
PLoS ONE  2014;9(1):e84997.
Because of its richness and availability, micro-blogging has become an ideal platform for conducting psychological research. In this paper, we proposed to predict active users' personality traits through micro-blogging behaviors. 547 Chinese active users of micro-blogging participated in this study. Their personality traits were measured by the Big Five Inventory, and digital records of micro-blogging behaviors were collected via web crawlers. After extracting 845 micro-blogging behavioral features, we first trained classification models utilizing Support Vector Machine (SVM), differentiating participants with high and low scores on each dimension of the Big Five Inventory. The classification accuracy ranged from 84% to 92%. We also built regression models utilizing PaceRegression methods, predicting participants' scores on each dimension of the Big Five Inventory. The Pearson correlation coefficients between predicted scores and actual scores ranged from 0.48 to 0.54. Results indicated that active users' personality traits could be predicted by micro-blogging behaviors.
PMCID: PMC3898945  PMID: 24465462
4.  A Two-Stage Association Study Suggests BRAP as a Susceptibility Gene for Schizophrenia 
PLoS ONE  2014;9(1):e86037.
Schizophrenia (SZ) is a neurodevelopmental disorder in which altered immune function typically plays an important role in mediating the effect of environmental insults and regulation of inflammation. The breast cancer suppressor protein associated protein (BRAP) is suggested to exert vital effects in neurodevelopment by modulating the mitogen-activated protein kinase cascade and inflammation signaling. To explore the possible role of BRAP in SZ, we conducted a two-stage study to examine the association of BRAP polymorphisms with SZ in the Han Chinese population. In stage one, we screened SNPs in BRAP from our GWAS data, which detected three associated SNPs, with rs3782886 being the most significant one (P  =  2.31E-6, OR  =  0.67). In stage two, we validated these three SNPs in an independently collected population including 1957 patients and 1509 controls, supporting the association of rs3782886 with SZ (P  =  1.43E-6, OR  =  0.73). Furthermore, cis-eQTL analysis indicates that rs3782886 genotypes are associated with mRNA levels of aldehyde dehydrogenase 2 family (ALDH2) (P  =  0.0039) and myosin regulatory light chain 2 (MYL2) (P < 1.0E-4). Our data suggest that the BRAP gene may confer vulnerability for SZ in Han Chinese population, adding further evidence for the involvement of developmental and/or neuroinflammatory cascades in the illness.
PMCID: PMC3893271  PMID: 24454952
5.  Role of the DLGAP2 Gene Encoding the SAP90/PSD-95-Associated Protein 2 in Schizophrenia 
PLoS ONE  2014;9(1):e85373.
Aberrant synaptic dysfunction is implicated in the pathogenesis of schizophrenia. The DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 (SAPAP2) located at the post-synaptic density of neuronal cells is involved in the neuronal synaptic function. This study aimed to investigate whether the DLGAP2 gene is associated with schizophrenia. We resequenced the putative promoter region and all the exons of the DLGAP2 gene in 523 patients with schizophrenia and 596 non-psychotic controls from Taiwan and conducted a case-control association analysis. We identified 19 known SNPs in this sample. Association analysis of 9 SNPs with minor allele frequency greater than 5% showed no association with schizophrenia. However, we found a haplotype (CCACCAACT) significantly associated with schizophrenia (odds ratio:2.5, p<0.001). We also detected 16 missense mutations and 1 amino acid-insertion mutation in this sample. Bioinformatic analysis showed some of these mutations were damaging or pathological to the protein function, but we did not find increased burden of these mutations in the patient group. Notably, we identified 5 private rare variants in 5 unrelated patients, respectively, including c.−69+9C>T, c.−69+13C>T, c.−69+47C>T, c.−69+55C>T at intron 1 and c.−32A>G at untranslated exon 2 of the DLGAP2 gene. These rare variants were not detected in 559 control subjects. Further reporter gene assay of these rare variants except c.−69+13C>T showed significantly elevated promoter activity than the wild type, suggesting increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia. Our results indicate that DLGAP2 is a susceptible gene of schizophrenia.
PMCID: PMC3885712  PMID: 24416398
6.  Outlier-Based Identification of Copy Number Variations Using Targeted Resequencing in a Small Cohort of Patients with Tetralogy of Fallot 
PLoS ONE  2014;9(1):e85375.
Copy number variations (CNVs) are one of the main sources of variability in the human genome. Many CNVs are associated with various diseases including cardiovascular disease. In addition to hybridization-based methods, next-generation sequencing (NGS) technologies are increasingly used for CNV discovery. However, respective computational methods applicable to NGS data are still limited. We developed a novel CNV calling method based on outlier detection applicable to small cohorts, which is of particular interest for the discovery of individual CNVs within families, de novo CNVs in trios and/or small cohorts of specific phenotypes like rare diseases. Approximately 7,000 rare diseases are currently known, which collectively affect ∼6% of the population. For our method, we applied the Dixon’s Q test to detect outliers and used a Hidden Markov Model for their assessment. The method can be used for data obtained by exome and targeted resequencing. We evaluated our outlier- based method in comparison to the CNV calling tool CoNIFER using eight HapMap exome samples and subsequently applied both methods to targeted resequencing data of patients with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. In both the HapMap samples and the TOF cases, our method is superior to CoNIFER, such that it identifies more true positive CNVs. Called CNVs in TOF cases were validated by qPCR and HapMap CNVs were confirmed with available array-CGH data. In the TOF patients, we found four copy number gains affecting three genes, of which two are important regulators of heart development (NOTCH1, ISL1) and one is located in a region associated with cardiac malformations (PRODH at 22q11). In summary, we present a novel CNV calling method based on outlier detection, which will be of particular interest for the analysis of de novo or individual CNVs in trios or cohorts up to 30 individuals, respectively.
PMCID: PMC3882271  PMID: 24400131
7.  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.
PMCID: PMC3909919  PMID: 24550797
maternal parenting oxytocin receptor gene; functional magnetic resonance imaging
8.  Effects of the Neurogranin Variant rs12807809 on Thalamocortical Morphology in Schizophrenia 
PLoS ONE  2013;8(12):e85603.
Although the genome wide supported psychosis susceptibility neurogranin (NRGN) gene is expressed in human brains, it is unclear how it impacts brain morphology in schizophrenia. We investigated the influence of NRGN rs12807809 on cortical thickness, subcortical volumes and shapes in patients with schizophrenia. One hundred and fifty six subjects (91 patients with schizophrenia and 65 healthy controls) underwent structural MRI scans and their blood samples were genotyped. A brain mapping algorithm, large deformation diffeomorphic metric mapping, was used to perform group analysis of subcortical shapes and cortical thickness. Patients with risk TT genotype were associated with widespread cortical thinning involving frontal, parietal and temporal cortices compared with controls with TT genotype. No volumetric difference in subcortical structures (hippocampus, thalamus, amygdala, basal ganglia) was observed between risk TT genotype in patients and controls. However, patients with risk TT genotype were associated with thalamic shape abnormalities involving regions related to pulvinar and medial dorsal nuclei. Our results revealed the influence of the NRGN gene on thalamocortical morphology in schizophrenia involving widespread cortical thinning and thalamic shape abnormalities. These findings help to clarify underlying NRGN mediated pathophysiological mechanisms involving cortical-subcortical brain networks in schizophrenia.
PMCID: PMC3875583  PMID: 24386483
9.  A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder 
PLoS ONE  2013;8(12):e81052.
Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.
Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.
The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.
Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders.
PMCID: PMC3861303  PMID: 24349030
10.  An Evaluation of Association between a Novel Hippocampal Biology Related SNP (rs7294919) and Schizophrenia 
PLoS ONE  2013;8(11):e80696.
Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919’s association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.
PMCID: PMC3838413  PMID: 24278305
11.  Polymorphism in Serotonin Receptor 3B Is Associated with Pain Catastrophizing 
PLoS ONE  2013;8(11):e78889.
Pain catastrophizing, a coping style characterized by excessively negative thoughts and emotions in relation to pain, is one of the psychological factors that most markedly predicts variability in the perception of pain; however, only little is known about the underlying neurobiology. The aim of this study was to test for associations between psychological variables, such as pain catastrophizing, anxiety and depression, and selected polymorphisms in genes related to monoaminergic neurotransmission, in particular serotonin pathway genes. Three hundred seventy-nine healthy participants completed a set of psychological questionnaires: the Pain Catastrophizing Scale (PCS), the State-Trait Anxiety Inventory and Beck’s Depression Inventory, and were genotyped for 15 single nucleotide polymorphisms (SNPs) in nine genes. The SNP rs1176744 located in the serotonin receptor 3B gene (5-HTR3B) was found to be associated with pain catastrophizing scores: both the global score and the subscales of magnification and helplessness. This is the first study to show an association between 5-HTR3B and PCS scores, thus suggesting a role of the serotonin pathway in pain catastrophizing. Since 5-HTR3B has previously been associated with descending pain modulation pathways, future studies will be of great interest to elucidate the molecular pathways involved in the relation between serotonin, its receptors and pain catastrophizing.
PMCID: PMC3823944  PMID: 24244382
12.  Associations of Serum Uric Acid and SLC2A9 Variant with Depressive and Anxiety Disorders: A Population-Based Study 
PLoS ONE  2013;8(10):e76336.
Limited information exists regarding the association between serum uric acid (SUA) and psychiatric disorders. We explored the relationship between SUA and subtypes of major depressive disorder (MDD) and specific anxiety disorders. Additionally, we examined the association of SLC2A9 rs6855911 variant with anxiety disorders.
We conducted a cross-sectional analysis on 3,716 individuals aged 35–66 years previously selected for the population-based CoLaus survey and who agreed to undergo further psychiatric evaluation. SUA was measured using uricase-PAP method. The French translation of the semi-structured Diagnostic Interview for Genetic Studies was used to establish lifetime and current diagnoses of depression and anxiety disorders according to the DSM-IV criteria.
Men reported significantly higher levels of SUA compared to women (357±74 µmol/L vs. 263±64 µmol/L). The prevalence of lifetime and current MDD was 44% and 18% respectively while the corresponding estimates for any anxiety disorders were 18% and 10% respectively. A quadratic hockey-stick shaped curve explained the relationship between SUA and social phobia better than a linear trend. However, with regards to the other specific anxiety disorders and other subtypes of MDD, there was no consistent pattern of association. Further analyses using SLC2A9 rs6855911 variant, known to be strongly associated with SUA, supported the quadratic relationship observed between SUA phenotype and social phobia.
A quadratic relationship between SUA and social phobia was observed consistent with a protective effect of moderately elevated SUA on social phobia, which disappears at higher concentrations. Further studies are needed to confirm our observations.
PMCID: PMC3812204  PMID: 24204615
13.  Functional Analysis of Deep Intronic SNP rs13438494 in Intron 24 of PCLO Gene 
PLoS ONE  2013;8(10):e76960.
The single nucleotide polymorphism (SNP) rs13438494 in intron 24 of PCLO was significantly associated with bipolar disorder in a meta-analysis of genome-wide association studies. In this study, we performed functional minigene analysis and bioinformatics prediction of splicing regulatory sequences to characterize the deep intronic SNP rs13438494. We constructed minigenes with A and C alleles containing exon 24, intron 24, and exon 25 of PCLO to assess the genetic effect of rs13438494 on splicing. We found that the C allele of rs13438494 reduces the splicing efficiency of the PCLO minigene. In addition, prediction analysis of enhancer/silencer motifs using the Human Splice Finder web tool indicated that rs13438494 induces the abrogation or creation of such binding sites. Our results indicate that rs13438494 alters splicing efficiency by creating or disrupting a splicing motif, which functions by binding of splicing regulatory proteins, and may ultimately result in bipolar disorder in affected people.
PMCID: PMC3805565  PMID: 24167553
14.  Galectin-3, a Marker of Cardiac Fibrosis, Predicts Incident Heart Failure in the Community 
We sought to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
PMCID: PMC3747668  PMID: 19025786
linkage analysis; association study; linkage disequilibrium; identity-by-descent (IBD)
21.  Functional Coding Variants in SLC6A15, a Possible Risk Gene for Major Depression 
PLoS ONE  2013;8(7):e68645.
SLC6A15 is a neuron-specific neutral amino acid transporter that belongs to the solute carrier 6 gene family. This gene family is responsible for presynaptic re-uptake of the majority of neurotransmitters. Convergent data from human studies, animal models and pharmacological investigations suggest a possible role of SLC6A15 in major depressive disorder. In this work, we explored potential functional variants in this gene that could influence the activity of the amino acid transporter and thus downstream neuronal function and possibly the risk for stress-related psychiatric disorders. DNA from 400 depressed patients and 400 controls was screened for genetic variants using a pooled targeted re-sequencing approach. Results were verified by individual re-genotyping and validated non-synonymous coding variants were tested in an independent sample (N = 1934). Nine variants altering the amino acid sequence were then assessed for their functional effects by measuring SLC6A15 transporter activity in a cellular uptake assay. In total, we identified 405 genetic variants, including twelve non-synonymous variants. While none of the non-synonymous coding variants showed significant differences in case-control associations, two rare non-synonymous variants were associated with a significantly increased maximal 3H proline uptake as compared to the wildtype sequence. Our data suggest that genetic variants in the SLC6A15 locus change the activity of the amino acid transporter and might thus influence its neuronal function and the risk for stress-related psychiatric disorders. As statistically significant association for rare variants might only be achieved in extremely large samples (N >70,000) functional exploration may shed light on putatively disease-relevant variants.
PMCID: PMC3712998  PMID: 23874702
22.  Cognitive Manic Symptoms in Bipolar Disorder Associated with Polymorphisms in the DAOA and COMT Genes 
PLoS ONE  2013;8(7):e67450.
Bipolar disorder is characterized by severe mood symptoms including major depressive and manic episodes. During manic episodes, many patients show cognitive dysfunction. Dopamine and glutamate are important for cognitive processing, thus the COMT and DAOA genes that modulate the expression of these neurotransmitters are of interest for studies of cognitive function.
Focusing on the most severe episode of mania, a factor was found with the combined symptoms of talkativeness, distractibility, and thought disorder, considered a cognitive manic symptoms (CMS) factor. 488 patients were genotyped, out of which 373 (76%) had talkativeness, 269 (55%) distractibility, and 372 (76%) thought disorder. 215 (44%) patients were positive for all three symptoms, thus showing CMS (Table 1). As population controls, 1,044 anonymous blood donors (ABD) were used. Case-case and case-control design models were used to investigate genetic associations between cognitive manic symptoms in bipolar 1 disorder and SNPs in the COMT and DAOA genes.
Clinical characteristics of the Bipolar 1 patient sample.
having all three symptoms: talkativeness, distractibility, and tought disorder.
The finding of this study was that cognitive manic symptoms in patients with bipolar 1 disorder was associated with genetic variants in the DAOA and COMT genes. Nominal association for DAOA SNPs and COMT SNPs to cognitive symptoms factor in bipolar 1 disorder was found in both allelic (Table 2) and haplotypic (Table 3) analyses. Genotypic association analyses also supported our findings. However, only one association, when CMS patients were compared to ABD controls, survived correction for multiple testing by max (T) permutation. Data also suggested interaction between SNPs rs2391191 in DAOA and rs5993883 in COMT in the case-control model.
Allelic association in bipolar 1 patients with cognitive manic symptoms (CMS) patients compared to non-CMS and to ABD controls in the DAOA and COMT genes.
SNP (minor allele(a)/major allele(b)).
gender and rs1718119 as covariate.
point-wise p-value from 10,000 pemutations with no covarite (EMP1).
corrected empirical p-value by max (T) permutation.
odds ratio (OR), the proportion of minor versus major allele affected (cognitive manic symptoms factor)/proportion of minor versus major allele unaffected (non-cognitive manic symptoms factor or ABD controls).
significant after correction for multiple testing by max (T) permutation.
Haplotype association of haplotype group 1 in bipolar 1 patients with cognitive manic symptoms (CMS) compared with non-CMS patients or ABD controls in the DAOA gene.
frequency (F) in sample.
gender and rs1718119 as covariates.
odds ratios (OR) for each haplotype.
Identifying genes associated with cognitive functioning has clinical implications for assessment of prognosis and progression. Our finding are consistent with other studies showing genetic associations between the COMT and DAOA genes and impaired cognition both in psychiatric disorders and in the general population.
PMCID: PMC3702534  PMID: 23861766
23.  Social Cognitive Role of Schizophrenia Candidate Gene GABRB2 
PLoS ONE  2013;8(4):e62322.
The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition.
PMCID: PMC3634734  PMID: 23638040
24.  Male-Biased Autosomal Effect of 16p13.11 Copy Number Variation in Neurodevelopmental Disorders 
PLoS ONE  2013;8(4):e61365.
Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49–16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.
PMCID: PMC3630198  PMID: 23637818
25.  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.
PMCID: PMC3629113  PMID: 23613972

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