European American Subjects Research Articles

Genome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations

Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with visual distortion and loss of visual acuity. We studied European American (EUR), African American (AFR), and Latino (admixed American, AMR) ERM participants in the Million Veteran Program (MVP) for genome-wide association analysis-a total of 38,232 case individuals and 557,988 control individuals. We completed a genome-wide association study (GWAS) in each population separately, and then results were meta-analyzed. Genome-wide significant (GWS) associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 in trans-ancestry meta-analysis. Many results replicated in the FinnGen sample. Several GWS variants associate to alterations in gene expression in the macula. ERM showed significant genetic correlation to multiple traits. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms for ERM.

Genetic and demographic predisposing factors associated with pediatric sleepwalking in the Philadelphia Neurodevelopmental Cohort

ObjectivesSleepwalking is a parasomnia associated with non-rapid eye movement (NREM) sleep and is formally diagnosed using polysomnography (PSG). However, PSG are difficult to perform on children or adolescents due to needed compliance. To understand this condition in youth, few studies have been conducted on a large cohort of youths with a diverse distribution of ages and races to characterize it better in the absence of PSG. The present study aimed to evaluate the prevalence of sleepwalking in youth, as well as associated demographic and genetic characteristics, using questionnaires in a large pediatric cohort. MethodsData from the Philadelphia Neurodevelopmental Cohort (PNC) of 7515 youths aged between 8 and 22 years were used in analyses. Demographic and clinical data, including age, sex, and race, and genetic data from 2753 African American (AA) and 4762 European American (EA) subjects were investigated. The age-wise prevalence of sleepwalking in AA and EA subjects was evaluated. Finally, race-specific genome-wide association (GWAS) analyses of sleepwalking were also performed (N = 155 AA cases and 2598 AA controls; N = 512 EA cases and 4250 EA controls). ResultsLifetime history of sleepwalking correlated with male sex and EA race. A genetic risk locus that reached genome-wide significance was detected at rs73450744 on chromosome 18 in AA, but not EA youth. ConclusionThe present results suggest that male sex, EA race, and genetic factors may be associated with higher rates of sleepwalking among youth. Future studies should consider these variables to advance understanding of the complex pathogenesis of sleepwalking.

Gene and protein expression in human megakaryocytes derived from induced pluripotent stem cells

BackgroundThere is interest in deriving megakaryocytes (MKs) from pluripotent stem cells (iPSC) for biological studies. We previously found that genomic structural integrity and genotype concordance is maintained in iPSC‐derived MKs. ObjectiveTo establish a comprehensive dataset of genes and proteins expressed in iPSC‐derived MKs. MethodsiPSCs were reprogrammed from peripheral blood mononuclear cells (MNCs) and MKs were derived from the iPSCs in 194 healthy European American and African American subjects. mRNA was isolated and gene expression measured by RNA sequencing. Protein expression was measured in 62 of the subjects using mass spectrometry. Results and ConclusionsMKs expressed genes and proteins known to be important in MK and platelet function and demonstrated good agreement with previous studies in human MKs derived from CD34+ progenitor cells. The percent of cells expressing the MK markers CD41 and CD42a was consistent in biological replicates, but variable across subjects, suggesting that unidentified subject‐specific factors determine differentiation of MKs from iPSCs. Gene and protein sets important in platelet function were associated with increasing expression of CD41/42a, while those related to more basic cellular functions were associated with lower CD41/42a expression. There was differential gene expression by the sex and race (but not age) of the subject. Numerous genes and proteins were highly expressed in MKs but not known to play a role in MK or platelet function; these represent excellent candidates for future study of hematopoiesis, platelet formation, and/or platelet function.

The spectrum of FVIII gene variants detected by next generation sequencing in 236 Chinese non-inversion hemophilia A pedigrees

IntroductionThe reported variants of hemophilia A are mainly from European subjects and American subjects of European descent, and limited data are available from more diverse ethnic backgrounds. This study was performed to identify the causative variants in a large HA cohort from Chinese population. Materials and methodsA total of 236 HA pedigrees were included. Molecular analysis of F8 gene was performed using next-generation sequencing (NGS) and then validated by Sanger sequencing and multiplex ligation probe amplification (MLPA) results. Variants were classified as pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign according to the American College of Medical Genetics and Genomics guidelines. ResultsA total of 186 F8 variants were identified, with 139 (139/186, 74.73%) point mutations, 44 (44/186, 23.66%) small insertions/deletions (InDels), and 3 (3/186, 1.61%) large deletions, they included 80 pathogenic and 84 likely pathogenic variants. Of these variants, 119 had been reported previously, and 67 were novel. No potentially causative mutations were found in the targeted F8 region in seventeen HA pedigrees. ConclusionsThe spectrum of F8 variants identified in this study provides additional information about HA and enriches our knowledge of the variant spectrum in a wider range of ethnic backgrounds.

Interactive Effects of HLA and GM Alleles on the Development of Alzheimer Disease.

ObjectiveWe investigated whether particular immunoglobulin GM (γ marker) alleles—individually or epistatically with a known human leukocyte antigen (HLA) risk allele—were associated with the development of Alzheimer disease (AD).MethodsUsing a prospective cohort study design, we genotyped DNA samples from 209 African American (AA) and 638 European American (EA) participants for IgG1 (GM 3 and GM 17), IgG2 (GM 23+ and GM 23−), and HLA-DRB1 rs9271192 (A/C) alleles by TaqMan and rhAMP genotyping assays.ResultsIn EA subjects, none of the GM or HLA alleles—individually or epistatically—were associated with time to development of AD. In AA subjects, GM and HLA alleles individually were not associated with time to development of AD. However, there was a significant interaction: In the presence of GM 3 (i.e., GM 3/3 and GM 3/17 subjects), the presence of the HLA-C allele was associated with a 4-fold increase in the likelihood of developing AD compared with its absence (hazard ratio [HR] 4.17, 95% CI, 1.28–13.58). In the absence of GM 3 (GM 17/17 subjects), however, the presence of the HLA-C allele was not associated with time to development of AD (HR 1.10, 95% CI, 0.50–2.41).ConclusionsThese results show that particular GM and HLA alleles epistatically contribute to the development of AD.

S173. GENOME-WIDE ASSOCIATION STUDIES OF SCHIZOPHRENIA AND BIPOLAR DISORDER IN A DIVERSE COHORT OF US VETERANS

BackgroundSchizophrenia and bipolar disorder are debilitating neuropsychiatric illnesses collectively affecting 2% of the world’s population, and which cause tremendous human suffering that impacts patients, their families and their communities. Recognizing the major impact of these disorders on the psychosocial function of more than 200,000 US Veterans, the Department of Veterans Affairs (VA) recently genotyping of nearly 9,000 veterans with schizophrenia or bipolar I disorder in Cooperative Studies Program (CSP) #572: “Genetics of Functional Disability in Schizophrenia and Bipolar Illness”, all of whom were extensively assessed for neurocognitive function and disability, and genotyped using a custom Affymetrix Axiom Biobank array.MethodsPrimary genome-wide association studies (GWAS) of schizophrenia and bipolar disorder were performed across and within ancestry goups, with attempted replication in matched subjects from the PGC and Genomic Psychiatry Cohort (GPC). We combined results for CSP#572 with available summary statistics from the PGC, Indonesia Schizophrenia Consortium and Genetic REsearch on schizophreniA neTwork-China and Netherland (GREAT-CN) study, and multi-ethnic GPC cohorts, achieving among the largest and most diverse studies of these disorders to date.ResultsPolygenic risk scores based on published PGC summary statistics for schizophrenia or bipolar disorder were significantly associated with case status among EA (P<10–30) and AA (P<0.0005) participants in CSP#572. Our primary analyses of schizophrenia yielded a single genome-wide significant association with variants in CHD7 at 8q12.2 for European-American (EA) participants, which remained significant in a joint analysis of EA and African-American (AA) subjects (P=4.62e-08). While no genome-wide significant associations were detected by our within-ancestry analyses of bipolar disorder, a cross-ancestry meta-analysis of CSP#572 participants yielded a significant finding at 10q25 with variants in SORCS3 (P=2.62e-08). Among loci attaining P<0.0001 in our within-ancestry analyses, 4 and 8 subsequently achieved genome-wide significance, respectively, when jointly analyzed with matched subjects from the PGC and GPC. Combining our results with published summary statistics, we performed a cross-ancestry GWAS meta-analysis of 69,280 schizophrenia cases and 138,379 controls, identifying 200 genome-wide significant loci of which 76 are newly reported here. Cross-ancestry analysis of 28,326 bipolar cases and 90,570 controls identified 24 genome-wide significant loci, including novel associations with common variants in PAX5, DOCK2, MACROD2, BRE, KCNG1, and LINC01378.DiscussionWe newly describe genome-wide analyses in a diverse cohort of US Veterans with schizophrenia or bipolar disorder, benchmarking the predictive value of polygenic risk scores based on published GWAS findings. Leveraging available summary statistics from studies of global populations, we add to burgeoning lists of genomic loci implicated in the etiologies of these disorders.

Population-Specific Patterns of Epigenetic Defects in the B Cell Lineage in Patients With Systemic Lupus Erythematosus.

To determine the stage of B cell development at which a systemic lupus erythematosus (SLE)-associated DNA methylation signature originates in African American (AA) and European American (EA) subjects, and to assess whether epigenetic defects in B cell development patterns could be predictive of SLE status in individual and mixed immune cell populations. B cells from AA patients (n = 31) and EA patients (n = 49) with or without SLE were sorted using fluorescence-activated cell sorting into 5 B cell subsets. DNA methylation, measured at ~460,000 CpG sites, was interrogated in each subset. Enrichment analysis of transcription factor interaction at SLE-associated methylation sites was performed. A random forests algorithm was used to identify an epigenetic signature of SLE in the B cell subsets, which was then validated in an independent cohort of AA and EA patients and healthy controls. Regression analysis across all B cell stages resulted in identification of 60 CpGs that reached genome-wide significance for SLE-associated methylation differences (P ≤ 1.07 × 10-7 ). Interrogation of ethnicity-specific CpGs associated with SLE revealed a hypomethylated pattern that was enriched for interferon (IFN)-regulated genes and binding of EBF1 in AA patients (each P < 0.001). AA patients with SLE could be distinguished from healthy controls when the predictive model developed with the transitional B cell subset was applied to other B cell subsets (mean receiver operating characteristic [ROC] area under the curve [AUC] 0.98), and when applied to CD19+ pan-B cells (mean ROC AUC 0.95) and CD4+ pan-T cells (mean ROC AUC 0.97) from the independent validation cohort. These results indicate that SLE-specific methylation patterns are ethnicity dependent. A pattern of epigenetic changes near IFN-regulated genes early in B cell development is a hallmark of SLE in AA female subjects. EBF1 binding sites are highly enriched for significant methylation changes, implying that this may be a potential regulator of SLE-associated epigenetic changes.

Genomewide Gene-by-Sex Interaction Scans Identify ADGRV1 for Sex Differences in Opioid Dependent African Americans

Sex differences in opioid dependence (OD) are genetically influenced. We conducted genomewide gene-by-sex interaction scans for the DSM-IV diagnosis of OD in 8,387 African-American (AA) or European-American subjects (43.6% women; 4,715 OD subjects). Among AAs, 9 SNPs were genome-wide significant at ADGRV1 (adhesion G-protein-coupled receptor V1, lead-SNP rs2366929*(C/T), p = 1.5 × 10−9) for sex-different risk of OD, with the rs2366929*C-allele increasing OD risk only for men. The top co-expressions in brain were between ADGRV1 and GRIK2 in substantia nigra and medullary inferior olivary nucleus, and between ADGRV1 and EFHC2 in frontal cortex and putamen. Significant sex-differential ADGRV1 expression from GTEx was detected in breast (Bonferroni-corrected-p < 0.002) and in heart (p < 0.0125), with nominal significance identified in brain, thyroid, lung, and stomach (p < 0.05). ADGRV1 co-expression and disease-enrichment analysis identifying the top 10 diseases showed strikingly sexually dimorphic risks. The enrichment and transcriptome analyses provided convergent support that ADGRV1 exerts a sex-different effect on OD risk. This is the first study to identify genetic variants contributing to sex differences in OD. It shows that ADGRV1 contributes to OD risk only in AA men, a finding that warrants further study.

Constitutively Higher Level of GSTT2 in Esophageal Tissues From African Americans Protects Cells Against DNA Damage

African American and European American individuals have a similar prevalence of gastroesophageal reflux disease (GERD), yet esophageal adenocarcinoma (EAC) disproportionately affects European American individuals. We investigated whether the esophageal squamous mucosa of African American individuals has features that protect against GERD-induced damage, compared with European American individuals. We performed transcriptional profile analysis of esophageal squamous mucosa tissues from 20 African American and 20 European American individuals (24 with no disease and 16 with Barrett's esophagus and/or EAC). We confirmed our findings in a cohort of 56patients and analyzed DNA samples from patients to identifyassociated variants. Observations were validated using matched genomic sequence and expression data from lymphoblasts from the 1000 Genomes Project. A panel of esophageal samples from African American and European American subjects was used to confirm allele-related differences in protein levels. The esophageal squamous-derived cell line Het-1A and a rat esophagogastroduodenal anastomosis model for reflux-generated esophageal damage were used to investigate the effects of the DNA-damaging agent cumene-hydroperoxide (cum-OOH) and a chemopreventive cranberry proanthocyanidin (C-PAC) extract, respectively, on levels of protein and messenger RNA (mRNA). We found significantly higher levels of glutathione S-transferase theta 2 (GSTT2) mRNA in squamous mucosa from African American compared with European American individuals and associated these with variants within the GSTT2 locus in African American individuals. We confirmed that 2 previously identified genomic variants at the GSTT2 locus, a 37-kb deletion and a 17-bp promoter duplication, reduce expression of GSTT2 in tissues from European American individuals. The nonduplicated 17-bp promoter was more common in tissue samples from populations of African descendant. GSTT2 protected Het-1A esophageal squamous cells from cum-OOH-induced DNA damage. Addition of C-PAC increased GSTT2 expression in Het-1A cells incubated with cum-OOH and in rats with reflux-induced esophageal damage. C-PAC also reduced levels of DNA damage in reflux-exposed rat esophagi, as observed by reduced levels of phospho-H2A histone family member X. We found GSTT2 to protect esophageal squamous cells against DNA damage from genotoxic stress and that GSTT2 expression can be induced by C-PAC. Increased levels of GSTT2 in esophageal tissues of African American individuals might protect them from GERD-induced damage and contribute to the low incidence of EAC in this population.

Clinical epidemiology of familial sarcoidosis: A systematic literature review.

Although the presence of familial sarcoidosis has been confirmed, clinical and epidemiological data on its characteristics are scattered and sometimes paradoxical. The objective of this review is to assess what is known on the clinical epidemiology of familial sarcoidosis, by combining data from early case reports with recent population based data; aiming to support in clinical decision making and providing information to patients. A systematic review of the literature in PubMed was done and 27 studies with clinical or epidemiological data on familial sarcoidosis, published between 1947 and 2017, were included. The pooled prevalence proportion of familial sarcoidosis, based on twelve study populations, was 9.5% (CI 4.6-16.1), highest in French, African American, Dutch and Irish patients. A heritability of 60-70% was estimated in diverse studies. Relative types and relationships most often reported in familial sarcoidosis were siblings and mother-child relationships. Familial risk is heterogeneous. In African Americans specific environmental factors have been associated with familial sarcoidosis (OR between 1.5 and 3.2). European American and African American subjects had different relative risks for first degree familial relationships (OR of 16.6 vs 3.1) and relative risk differed between relative types. Clinical findings in familial sarcoidosis are still obscure. Prevalence of familial sarcoidosis is high in specific study populations from countries worldwide. The estimated heritability of 60-70%, suggests a shared determinant, and the heterogeneous familial risk, associated with both genetic and environmental factors. Familial relative risks and clinical phenotypes may differ between ethnic groups and relative types, but require further study.

Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

BackgroundLoss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. ObjectivesThe goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. MethodsWhole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. ResultsAmong 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). ConclusionsFunctionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

Overcoming Tribalism

Overcoming Tribalism

Abstract 372: Obesity matters: Prostate cancers that overexpress fatty acid binding protein 5 are more common in men who are overweight or obese

Abstract BACKGROUND: One of the hallmarks of the malignant phenotype is an increase in the cell's demand for fatty acids (FA). Many cancers, including prostate cancer, show increased expression of fatty acid synthase (FASN), a multi-component enzyme that catalyzes the de novo synthesis of the fatty acid palmitate. However recent observations suggest that alternate mechanisms for FA acquisition are also important, including the utilization of exogenous palmitate when it's available. Recently, through a biopsy-based molecular analysis of high risk prostate cancer, we identified a tumor subtype with very high (&amp;gt;10 fold) "outlier" overexpression of fatty acid binding protein 5 (FABP5). FABP5 is involved in lipid transport and signaling, and it facilitates the utilization of palmitate and other FAs from outside of the cell. De novo palmitate synthesis by the FASN pathway is energetically expensive compared to utilization of exogenous fatty acids. STUDY DESIGN: We proposed that prostate cancers that can efficiently utilize exogenous palmitate are at a selective advantage when dietary FAs are abundant. In this study, to test that hypothesis, we compared FABP5 and FASN expression levels in prostate cancers obtained from diagnostic biopsies from normal weight, overweight and obese study subjects. A total of 201 consecutive eligible prostate biopsy patients were prospectively enrolled; 151 (75%) of these patients were cancer positive. Prostate cancer FABP5 and FASN mRNA expression were measured by qrtPCR and FABP5/FASN and FASN/FABP5 expression ratios were determined for each cancer positive core. BMI and self-identified race were obtained from hospital records. RESULTS: The expression of FABP5 and the FABP5/FASN expression ratio were significantly higher in overweight and obese individuals compared to normal weight individuals (mean FABP5/FASN overexpression ratio of 20.2 in overweight/obese subjects vs 4.0 in normal weight subjects; p &amp;lt; 0.05). The highest levels of prostate cancer FABP5 outlier overexpression (FABP5/FASN &amp;gt; 100) were observed in African American subjects with BMI &amp;gt; 30, and high levels of FABP5 outlier overexpression were more strongly associated with overall Gleason sum in African American than in European American subjects. CONCLUSIONS: In our study population, prostate cancer subtypes with high levels of FABP5 overexpression were more common in biopsy patients who were overweight or obese compared to normal weight patients. The highest levels of FABP5 overexpression in were observed in prostate cancers from obese African American subjects. Such FABP5 dominant prostate cancers may utilize exogenous fatty acids more efficiently and be more sensitive to dietary interventions than the more widely studied FASN dominant prostate cancers. Funding: DOD Prostate Cancer Research Program Awards W8XWH-10-1-0543 (Grizzle, PI) and W81XWH-10-1-0544 (Gaston, PI) Citation Format: Sandra M. Gaston, Soroush Rais-Bahrami, James Kearns, Dennis Otali, Denise Oelschlager, Mark S. DeGuenther, Jeffrey W. Nix, Peter N. Kolettis, James E. Bryant, Robert A. Oster, William E. Grizzle. Obesity matters: Prostate cancers that overexpress fatty acid binding protein 5 are more common in men who are overweight or obese [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 372.

Genome‐wide association study of cognitive flexibility assessed by the Wisconsin Card Sorting Test

Cognitive flexibility is a critical component of executive function and is strongly influenced by genetic factors. We conducted a genome-wide association study of cognitive flexibility (as measured by perseverative errors on the Wisconsin Card Sorting Test) in two sets of African American (AA) and European American (EA) subjects (Yale-Penn-1: 1,411 AAs/949 EAs; Yale-Penn-2: 1,178 AAs/1,335 EAs). We examined the association of cognitive flexibility with genotyped or imputed SNPs across the genome. In AAs, two correlated common single nucleotide polymorphisms (SNPs) (rs7165213/rs35633795) in the downstream region of the noncoding gene LOC101927286 on chromosome 15 showed genome-wide significant (GWS) associations with cognitive flexibility (Yale-Penn-1: p = 6.0 × 10-9 /1.3 × 10-8 ; Yale-Penn-2: p = .029/.010; meta-analysis: p = 4.2 × 10-7 /1.0 × 10-7 ) in the same effect direction. In EAs, no GWS associations were observed. Enriched gene sets identified by Data-driven Expression-Prioritized Integration for Complex Traits (DEPICT) analysis of the top SNPs (pmeta-analysis < 10-5 ) included the signalosome and ubiquitin-specific peptidase 9, X-linked (USP9X) subnetwork in AAs, and abnormal frontal and occipital bone morphology in EAs. We also performed polygenic risk score (PRS) analysis to examine the genetic correlation of cognition-proxy phenotypes (general cognitive function, education attainment, childhood intelligence, and infant head circumference) and cognitive flexibility in EAs. The PRS derived from general cognitive function-associated SNPs was significantly associated with cognitive flexibility. Nongenetic factors (age, education, sex, and tobacco recency) also exerted significant effects on cognitive flexibility. Our study demonstrates that both genetic and nongenetic factors impact cognitive flexibility, and variants in genes involved in protein degradation and brain development may contribute to population variation in cognitive function.

Ancestry-specific and sex-specific risk alleles identified in a genome-wide gene-by-alcohol dependence interaction study of risky sexual behaviors.

We previously mapped loci for the genome-wide association studies (GWAS) and genome-wide gene-by-alcohol dependence interaction (GW-GxAD) analyses of risky sexual behaviors (RSB). This study extends those findings by analyzing the ancestry- and sex-specific AD-stratified effects on RSB. We examined the concordance of findings for the AD-stratified GWAS and the GW-GxAD analysis of RSB, with concordance defined as genome-wide significance in one analysis and at least nominal significance in the second analysis. A total of 2,173 African-American (AA) and 1,751 European-American (EA) subjects were investigated. Information regarding RSB (lifetime experiences of unprotected sex and multiple sexual partners) and DSM-IV diagnosis of lifetime AD were derived from the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). In our ancestry- and sex-specific analyses, we identified four independent genome-wide significant (GWS) loci (p < 5*10-8 ) and one suggestive locus (p < 6*10-8 ). In men, we observed a GWS signal in FAM162A (rs2002594, p = 4.96*10-8 ). In women, there was a suggestive locus in PLGRKT (rs3824435, p = 5.52*10-8 ). In AAs, there was a GWS signal in GRK5 (rs1316543, p = 1.25*10-9 ). In AA men, we observed an intergenic GWS signal (rs12898370, p = 4.49*10-8 ) near LINGO1. In EA men, there was a GWS signal in CCSER1 (rs62313897; p = 7.93*10-10 ). The loci identified in this GWAS implicate molecular mechanisms related to psychiatric illness and personality features, suggesting that the interplay between AD and RSB is mediated by alleles associated with behavioral traits.

The Pharmacogenomics of Bipolar Disorder Study: A Combined Analysis Of Ips Neuronal Expression And Gwas Data Identifies Cbarp And Card19 As Associated With Lithium Response

Background Lithium was the first mood stabilizing medication and remains the most effective. A variety of data argue that lithium responsive bipolar disorder may be genetically distinct and hence lithium response may be a powerful probe distinguishing different forms of illness. The Pharmacogenomics of Bipolar Disorder study has recently completed a prospective trial of lithium in order to quantify lithium response in 585 subjects with bipolar I disorder and conducted a GWAS on this sample. We have also recently reported that iPS derived glutamatergic hippocampal neurons demonstrated a 4 fold higher spontaneous firing rate that was reversed by lithium, but only in cells from lithium responders. Realizing that it was very difficult to obtain GWAS-size samples from a prospective trial, the PGBD study was originally designed to use functional data from stem cell derived neurons in order to reduce the number of statistical tests. Methods 11 sites participated in a 2.5 year prospective trial of lithium in bipolar I subjects. After written informed consent and 4 months of stabilization, subjects were followed for 2 years on monotherapy. Response was quantified as time to relapse. 585 subjects were genotyped using the Illumina PsychArray. A pilot GWAS of 321 European American subjects was conducted using plink and principal components from ancestry markers. RNAseq was conducted on all the iPS experiments in which lithium or control was applied to hyperexcitable cells. Expression was analyzed and compared using EdgeR in the Bioconductor package. Results Genes were selected from the iPS RNAseq data that underwent a significant change in expression in response to lithium, but only in cells from lithium responders. This yielded a list of 469 genes which were then compared with brain eQTL databases. 143 of these genes had known variants affecting expression in brain. Of these 143 SNPs, 27 were directly genotyped. The GWAS p values for these 27 SNPs were examined and one SNP was identified (rs621071) on chromosome 1 that regulates a gene on chromosome 9 (CBARP) and a gene on chromosome 19 (CARD19). This SNP showed significant association to lithium response after Bonferroni correction for the much smaller number of tests (p=0.026). Discussion The combined analysis of GWAS and functional studies make possible genomewide analyses of smaller more difficult to phenotype samples. CBARP is a very interesting candidate that binds to CACNA1C and modulates current through L-type voltage gated calcium channels as have been implicated in bipolar disorder. The function of CARD19 is less clear but may involve inhibition of Bcl-10. Lastly, these results suggest that drug response may be a powerful phenotype with which to dissect different cellular mechanisms in bipolar disorder.

Demonstration of Protein-Based Human Identification Using the Hair Shaft Proteome.

Human identification from biological material is largely dependent on the ability to characterize genetic polymorphisms in DNA. Unfortunately, DNA can degrade in the environment, sometimes below the level at which it can be amplified by PCR. Protein however is chemically more robust than DNA and can persist for longer periods. Protein also contains genetic variation in the form of single amino acid polymorphisms. These can be used to infer the status of non-synonymous single nucleotide polymorphism alleles. To demonstrate this, we used mass spectrometry-based shotgun proteomics to characterize hair shaft proteins in 66 European-American subjects. A total of 596 single nucleotide polymorphism alleles were correctly imputed in 32 loci from 22 genes of subjects’ DNA and directly validated using Sanger sequencing. Estimates of the probability of resulting individual non-synonymous single nucleotide polymorphism allelic profiles in the European population, using the product rule, resulted in a maximum power of discrimination of 1 in 12,500. Imputed non-synonymous single nucleotide polymorphism profiles from European–American subjects were considerably less frequent in the African population (maximum likelihood ratio = 11,000). The converse was true for hair shafts collected from an additional 10 subjects with African ancestry, where some profiles were more frequent in the African population. Genetically variant peptides were also identified in hair shaft datasets from six archaeological skeletal remains (up to 260 years old). This study demonstrates that quantifiable measures of identity discrimination and biogeographic background can be obtained from detecting genetically variant peptides in hair shaft protein, including hair from bioarchaeological contexts.

Age-Related Changes in Segmental Body Composition by Ethnicity and History of Weight Change across the Adult Lifespan.

This study assessed age-related changes in body composition (specifically in trunk fat and appendicular lean masses), with consideration of body mass index (BMI) at age 20 years (BMI reference age, “BMIref”), ethnicity and lifetime weight change history. A cross-sectional dual-energy X-ray absorptiometry-based dataset was extracted from the U.S. National Health and Nutrition Examination Survey (NHANES) 1999–2004. Only European-American and African-American subjects were used (2705 men, 2527 women). For each gender and ethnicity, 6 analytic cases were considered, based on three BMIref categories (normal, overweight and obese, being 22, 27 and 30 kg/m2, respectively) and two weight contexts (stable weight or weight gain across the lifespan). A nonparametric model was developed to investigate age-related changes in body composition. Then, parametric modelling was developed for assessing BMIref- and ethnicity-specific effects during aging. In the stable weight, both genders’ and ethnicities’ trunk fat (TF) increased gradually; body fat (BF) remained stable until 40 years and increased thereafter; trunk lean (TL) remained stable, but appendicular lean (APL) and body lean (BL) declined from 20 years. In the weight gain context, TF and BF increased at a constant rate, while APL, TL and BL increased until 40–50 years, and then declined slightly. Compared with European-American subjects of both genders, African-American subjects had lower TF and BF masses. Ethnic differences in body composition were quantified and found to remain constant across the lifespan.

Multiethnic genome-wide association study identifies ethnic-specific associations with body mass index in Hispanics and African Americans

BackgroundGenome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ​ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings ​across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women’s Health Initiative (WHI).ResultsWe identified a genome-wide significant association in MESA Hispanics—rs12253976 in KLF6 (beta = 5.792 kg/m2 per-allele, 95 % confidence interval (CI): 3.885, 7.698; p = 3.43 × 10−9)—and suggestive SNPs with p < 5 × 10−6 in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta = −1.111 kg/m2, 95 % CI: −1.578, −0.645; p = 3.33 × 10−6) and WHI Hispanics (beta = −0.304 kg/m2, 95 % CI: −0.613, 0.006; p = 0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10−3) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta = 1.104 kg/m2, 95 % CI: 0.643, 1.564; p = 2.85 × 10−6) and WHI African Americans (beta = 0.219 kg/m2, 95 % CI: −0.021, 0.460; p = 0.074).ConclusionsTwo BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0387-0) contains supplementary material, which is available to authorized users.

Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among asthmatic subjects

Inhaled corticosteroids (ICSs) are the preferred treatment for achieving asthma control. However, little is known regarding the factors contributing to treatment response and whether treatment response differs by population group. We sought to assess behavioral, sociodemographic, and genetic factors related to ICS response among African American and European American subjects with asthma. Study participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). The analytic sample included asthmatic subjects aged 12 to 56years with greater than 12% bronchodilator reversibility and percent predicted FEV1 of between 40% and 90%. Participants received 6weeks of inhaled beclomethasone dipropionate. The primary measure of ICS response was a change in Asthma Control Test (ACT) score; the secondary measure was a change in prebronchodilator FEV1. Adherence was measured with electronic monitors. Genetic ancestry was estimated for African American participants by using genome-wide genotype data. There were 339 study participants; 242 self-identified as African American and 97 as European American. Baseline ACT score, percent predicted FEV1, degree of bronchodilator response, and ICS adherence were significantly associated with ICS response. Abaseline ACT score of 19 or less was useful in identifying those who would respond, as evidenced by the significant dose-response relationship with ICS adherence. Neither self-reported race-ethnicity among all participants nor proportion of African ancestry among African American participants was associated with ICS responsiveness. Our findings suggest that baseline lung function measures and self-reported asthma control predict ICS response, whereas self-reported race-ethnicity and genetic ancestry do not.