Differences In Genetic Risk Research Articles

Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10–100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10−16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations.

Evolutionary Perspectives on Genetic and Environmental Risk Factors for Psychiatric Disorders

Evolutionary medicine uses evolutionary theory to help elucidate why humans are vulnerable to disease and disorders. I discuss two different types of evolutionary explanations that have been used to help understand human psychiatric disorders. First, a consistent finding is that psychiatric disorders are moderately to highly heritable, and many, such as schizophrenia, are also highly disabling and appear to decrease Darwinian fitness. Models used in evolutionary genetics to understand why genetic variation exists in fitness-related traits can be used to understand why risk alleles for psychiatric disorders persist in the population. The usual explanation for species-typical adaptations-natural selection-is less useful for understanding individual differences in genetic risk to disorders. Rather, two other types of models, mutation-selection-drift and balancing selection, offer frameworks for understanding why genetic variation in risk to psychiatric (and other) disorders exists, and each makes predictions that are now testable using whole-genome data. Second, species-typical capacities to mount reactions to negative events are likely to have been crafted by natural selection to minimize fitness loss. The pain reaction to tissue damage is almost certainly such an example, but it has been argued that the capacity to experience depressive symptoms such as sadness, anhedonia, crying, and fatigue in the face of adverse life situations may have been crafted by natural selection as well. I review the rationale and strength of evidence for this hypothesis. Evolutionary hypotheses of psychiatric disorders are important not only for offering explanations for why psychiatric disorders exist, but also for generating new, testable hypotheses and understanding how best to design studies and analyze data.

A case of a four-year-old child adopted at eight months with unusual mood patterns and significant polypharmacy

BackgroundLong-term effects of neglect in early life are still widely unknown. Diversity of outcomes can be explained by differences in genetic risk, epigenetics, prenatal factors, exposure to stress and/or substances, and parent-child interactions. Very common sub-threshold presentations of children with history of early trauma are challenging not only to diagnose but also in treatment.Case presentationA Caucasian 4-year-old, adopted at 8 months, male patient with early history of neglect presented to pediatrician with symptoms of behavioral dyscontrol, emotional dysregulation, anxiety, hyperactivity and inattention, obsessions with food, and attachment issues. He was subsequently seen by two different child psychiatrists. Pharmacotherapy treatment attempted included guanfacine, fluoxetine and amphetamine salts as well as quetiapine, aripiprazole and thioridazine without much improvement. Risperidone initiated by primary care seemed to help with his symptoms of dyscontrol initially but later the dose had to be escalated to 6 mg total for the same result. After an episode of significant aggression, the patient was admitted to inpatient child psychiatric unit for stabilization and taper of the medicine.ConclusionsThe case illustrates difficulties in management of children with early history of neglect. A particular danger in this patient population is polypharmacy, which is often used to manage transdiagnostic symptoms that significantly impacts functioning with long term consequences.

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes

BackgroundIn adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as ‘latent autoimmune diabetes in adults’ (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes.MethodsWe tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls.ResultsOverall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted.ConclusionLADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.

The rs4646 and rs12592697 Polymorphisms in CYP19A1 Are Associated with Disease Progression among Patients with Breast Cancer from Different Racial/Ethnic Backgrounds.

Given the racial/ethnic disparities in breast cancer, we evaluated the association between CYP19A1 single nucleotide polymorphisms (SNPs) on disease progression in women with breast cancer from different racial/ethnic backgrounds. This is a cross-sectional analysis of data from 327 women with breast cancer in the Expanded Breast Cancer Registry program of the University of New Mexico. Stored DNA samples were analyzed for CYP19A1 SNPs using a custom designed microarray panel. Genotype-phenotype correlations were analyzed. Of the 384 SNPs, 2 were associated with clinically significant outcomes, the rs4646 and rs12592697. The T allele for the rs4646 was associated with advanced stage of the disease at the time of presentation (odds ratio [OR]:1.8, confidence intervals [CI]: 1.05–3.13, p < 0.05) and a more progressive disease (OR: 2.1 [CI: 1.1–4.0], p = 0.04). For the rs12592697, the variant T allele was more frequent in Hispanic women and associated with a more progressive disease (OR: 2.05 [CI: 1.0–4.0], p = 0.04). However, further analysis according to menopausal status showed that the association between these 2 SNPs with disease progression or the stage at diagnosis are confined only to postmenopausal women. The odds ratios of disease progression among postmenopausal women carrying the T allele for the rs4646 and rs12592697 are 3.05 (1.21, 7.74, p = 0.02) and 3.80 (1.24, 11.6, p = 0.02), respectively. Regardless, differences in disease progression among the different genotypes for both SNPs disappeared after adjustment for treatment. In summary, the rs4646 and the rs12592697 SNPs in CYP19A1 are associated with differences in disease progression in postmenopausal women. However, treatment appears to mitigate the differences in genetic risk.

Association between polygenic risk for schizophrenia, neurocognition and social cognition across development.

Breakthroughs in genomics have begun to unravel the genetic architecture of schizophrenia risk, providing methods for quantifying schizophrenia polygenic risk based on common genetic variants. Our objective in the current study was to understand the relationship between schizophrenia genetic risk variants and neurocognitive development in healthy individuals. We first used combined genomic and neurocognitive data from the Philadelphia Neurodevelopmental Cohort (4303 participants ages 8–21 years) to screen 26 neurocognitive phenotypes for their association with schizophrenia polygenic risk. Schizophrenia polygenic risk was estimated for each participant based on summary statistics from the most recent schizophrenia genome-wide association analysis (Psychiatric Genomics Consortium 2014). After correction for multiple comparisons, greater schizophrenia polygenic risk was significantly associated with reduced speed of emotion identification and verbal reasoning. These associations were significant by age 9 years and there was no evidence of interaction between schizophrenia polygenic risk and age on neurocognitive performance. We then looked at the association between schizophrenia polygenic risk and emotion identification speed in the Harvard/MGH Brain Genomics Superstruct Project sample (695 participants ages 18–35 years), where we replicated the association between schizophrenia polygenic risk and emotion identification speed. These analyses provide evidence for a replicable association between polygenic risk for schizophrenia and a specific aspect of social cognition. Our findings indicate that individual differences in genetic risk for schizophrenia are linked with the development of aspects of social cognition and potentially verbal reasoning, and that these associations emerge relatively early in development.

Reduced specialized processing in psychotic disorder: a graph theoretical analysis of cerebral functional connectivity.

BackgroundPrevious research has shown that the human brain can be represented as a complex functional network that is characterized by specific topological properties, such as clustering coefficient, characteristic path length, and global/local efficiency. Patients with psychotic disorder may have alterations in these properties with respect to controls, indicating altered efficiency of network organization. This study examined graph theoretical changes in relation to differential genetic risk for the disorder and aimed to identify clinical correlates.MethodsAnatomical and resting‐state MRI brain scans were obtained from 73 patients with psychotic disorder, 83 unaffected siblings, and 72 controls. Topological measures (i.e., clustering coefficient, characteristic path length, and small‐worldness) were used as dependent variables in a multilevel random regression analysis to investigate group differences. In addition, associations with (subclinical) psychotic/cognitive symptoms were examined.ResultsPatients had a significantly lower clustering coefficient compared to siblings and controls, with no difference between the latter groups. No group differences were observed for characteristic path length and small‐worldness. None of the topological properties were associated with (sub)clinical psychotic and cognitive symptoms.ConclusionsThe reduced ability for specialized processing (reflected by a lower clustering coefficient) within highly interconnected brain regions observed in the patient group may indicate state‐related network alterations. There was no evidence for an intermediate phenotype and no evidence for psychopathology‐related alterations.

An animal model of differential genetic risk for methamphetamine intake.

The question of whether genetic factors contribute to risk for methamphetamine (MA) use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine-associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the development of a binge model of MA intake, examining the effect of withdrawal from chronic MA on MA intake, and studying potential Taar1 gene × gene and gene × environment interactions. These and other studies are intended to improve our genetic model with regard to its translational value to human addiction.

Which alcohol use disorder criteria contribute to the association of ADH1B with alcohol dependence?

Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM-IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding.

Methamphetamine drinking microstructure in mice bred to drink high or low amounts of methamphetamine

Genetic factors likely influence individual sensitivity to positive and negative effects of methamphetamine (MA) and risk for MA dependence. Genetic influence on MA consumption has been confirmed by selectively breeding mouse lines to consume high (MAHDR) or low (MALDR) amounts of MA, using a two-bottle choice MA drinking (MADR) procedure. Here, we employed a lickometer system to characterize the microstructure of MA (20, 40, and 80mg/l) and water intake in MAHDR and MALDR mice in 4-h limited access sessions, during the initial 4hours of the dark phase of their 12:12h light:dark cycle. Licks at one-minute intervals and total volume consumed were recorded, and bout analysis was performed. MAHDR and MALDR mice consumed similar amounts of MA in mg/kg on the first day of access, but MAHDR mice consumed significantly more MA than MALDR mice during all subsequent sessions. The higher MA intake of MAHDR mice was associated with a larger number of MA bouts, longer bout duration, shorter interbout interval, and shorter latency to the first bout. In a separate 4-h limited access MA drinking study, MALDR and MAHDR mice had similar blood MA levels on the first day MA was offered, but MAHDR mice had higher blood MA levels on all subsequent days, which corresponded with MA intake. These data provide insight into the microstructure of MA intake in an animal model of differential genetic risk for MA consumption, which may be pertinent to MA use patterns relevant to genetic risk for MA dependence.

Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease

Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions. While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

Analysis of Gender Differences in Genetic Risk: Association of TNFAIP3 Polymorphism with Male Childhood-Onset Systemic Lupus Erythematosus in the Japanese Population

BackgroundSystemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies.Methodology/Principal FindingsThe 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46–11.2 P<0.05).ConclusionsAssociations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.

Association studies of TNFSF4, TNFAIP3 and FAM167A-BLK polymorphisms with primary Sjogren’s syndrome in Han Chinese

Single-nucleotide polymorphisms (SNPs) in the TNFSF4, TNFAIP3 and FAM167A-BLK genes have been associated with several autoimmune diseases. Associations of TNFSF4 and FAM167A-BLK with primary Sjogren's syndrome (pSS) have also been described in a Caucasian population. However, it remains unknown whether polymorphisms of TNFSF4, TNFAIP3 and FAM167A-BLK are associated with pSS in Han Chinese. This study aimed to determine whether SNPs in TNFSF4, TNFAIP3 or FAM167A-BLK genetically predispose a Chinese Han population to pSS. Ten SNPs in the TNFSF4 region (rs1234315, rs2205960, rs844648 and rs704840), the TNFAIP3 gene (rs5029939 and rs2230926) and the FAM167A-BLK region (rs7812879, rs2254546, rs2618479 and rs2248932) were genotyped in a cohort of 555 pSS patients and 597 healthy controls, by using the Sequenom MassArray system. Weak associations were observed when the SNPs in TNFSF4 (rs2205960, rs844648 and rs704840) and FAM167A-BLK (rs7812879, rs2254546 and rs2618479) were directly analyzed or analyzed under dominant model between pSS and controls (all P<0.05). However, when Bonferroni correction was applied to the multiple comparisons, all of the associations vanished, except for rs7812879 (Pa=0.045). The frequencies of alleles, genotypes and haplotypes of TNFAIP3 SNPs and rs2248932 of FAM167A-BLK were not significantly different between the pSS patients and controls. No epistatic interactions were found to exist between the SNPs examined. Unlike the SNPs in TNFAIP3 and TNFSF4, rs7812879 in FAM167A-BLK imparts susceptibility to pSS in a Han Chinese population. The differential genetic risk profiles from other autoimmune diseases may indicate differential molecular mechanisms underlying pSS pathogenesis in this group.

The Genomic Revolution and Beliefs about Essential Racial Differences: A Backdoor to Eugenics?

Could the explosion of genetic research in recent decades affect our conceptions of race? In Backdoor to Eugenics, Duster argues that reports of specific racial differences in genetic bases of disease, in part because they are presented as objective facts whose social implications are not readily apparent, may heighten public belief in more pervasive racial differences. We tested this hypothesis with a multi-method study. A content analysis showed that news articles discussing racial differences in genetic bases of disease increased significantly between 1985 and 2008 and were significantly less likely than non-health-related articles about race and genetics to discuss social implications. A survey experiment conducted with a nationally representative sample of 559 adults found that a news-story vignette reporting a specific racial difference in genetic risk for heart attacks (the Backdoor Vignette) produced significantly greater belief in essential racial differences than did a vignette portraying race as a social construction or a no-vignette condition. The Backdoor Vignette produced beliefs in essential racial differences that were virtually identical to those produced by a vignette portraying race as a genetic reality. These results suggest that an unintended consequence of the genomic revolution may be the reinvigoration of age-old beliefs in essential racial differences.

Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia among African Americans

AbstractThe incidence of chronic lymphocytic leukemia (CLL) is significantly lower in African Americans than whites, but overall survival is inferior. The biologic basis for these observations remains unexplored. We hypothesized that germline genetic predispositions differ between African Americans and whites with CLL and yield inferior clinical outcomes among African Americans. We examined a discovery cohort of 42 African American CLL patients ascertained at Duke University and found that the risk allele frequency of most single nucleotide polymorphisms known to confer risk of development for CLL is significantly lower among African Americans than whites. We then confirmed our results in a distinct cohort of 68 African American patients ascertained by the CLL Research Consortium. These results provide the first evidence supporting differential genetic risk for CLL between African Americans compared with whites. A fuller understanding of differential genetic risk may improve prognostication and therapeutic decision making for all CLL patients.

Male Germline Transmits Fetal Alcohol Adverse Effect on Hypothalamic Proopiomelanocortin Gene Across Generations

Neurons containing proopiomelanocortin (POMC)-derived peptides, known to control stress axis, metabolic, and immune functions, have a lower function in patients with a family history of alcoholism, raising the possibility that alcohol effects on the POMC system may transmit through generations. Here we describe epigenetic modifications of Pomc gene that transmit through generation via male germline and may be critically involved in alcoholism-inherited diseases. Whether an epigenetic mechanism is involved in causing a Pomc expression deficit in fetal alcohol-exposed rats is studied by determining Pomc gene methylation, expression, and functional abnormalities and their normalization following suppression of DNA methylation or histone acetylation. Additionally, transgenerational studies were conducted to evaluate the germline-transmitted effect of alcohol. Fetal alcohol-exposed male and female rat offspring showed a significant deficit in POMC neuronal functions. Associated with this was an increased methylation status of several CpG dinucleotides in the proximal part of the Pomc promoter region and altered level of histone-modifying proteins and DNA methyltransferases levels in POMC neurons. Suppression of histone deacetylation and DNA methylation normalized Pomc expression and functional abnormalities. Fetal alcohol-induced Pomc gene methylation, expression, and functional defects persisted in the F2 and F3 male but not in female germline. Additionally, the hypermethylated Pomc gene was detected in sperm of fetal alcohol-exposed F1 offspring that was transmitted through F3 generation via male germline. Trangenerational epigenetic studies should spur new insight into the biological mechanisms that influence the sex-dependent difference in genetic risk of alcoholism-inherited diseases.

Selections from the Current Literature

As noted by the authors of this study, environmental and behavioral factors that affect dental caries development such as exposure to fluoride and frequency of tooth-brushing and eating snack foods appear to be different for smooth-surface caries than for pit and fissure caries. Moreover, although there is increasing evidence that genetic factors can increase the risk of experiencing caries, it is not known if there are differences in genetic risk between caries in tooth surfaces with pits and fissures and caries in smooth tooth surfaces. The purpose of this study was to determine if genetic risk varies between caries in these two types of dental surfaces.

Population Differences in Genetic Risk for Age-Related Macular Degeneration and Implications for Genetic Testing

To the Editor: The personal genetics revolution has promised patients an accounting of their individual risk of common, complex diseases based on their DNA sequence. Though under increased scrutiny from the Food and Drug Administration, several direct-to-consumer (DTC) genetic testing companies offer such services, and conflicting results for the same disease in the same individual are commonly reported1. Even for an unusual case like age-related macular degeneration (AMD) for which a small number of loci with strong effects has consistently replicated across studies, it is extremely difficult to predict who will or will not develop disease2. Furthermore, most genetic association studies have been conducted in European Americans, and because the frequency of genetic polymorphisms varies across race-ethnicities, the predictive value of any genetic algorithm developed in one population may not translate to another. We have seen an extreme example of this for the ARMS2 AMD susceptibility locus. The non-synonymous coding variant A69S within ARMS2 is one of the strongest genetic risk factors for AMD (odds ratios (OR) ~2.2 in heterozygotes, ~7.1 in homozygotes3 in European Americans). This variant (or others in strong linkage disequilibrium with it) has been used in predictive algorithms published in the scientific literature2, 4, marketed by DTC companies, and in the Macula Risk™ test available by physician order.

Race As a Determinant of Disease Biology and Outcomes in Chronic Lymphocytic Leukemia

Abstract 1785 Background:Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the progressive clonal expansion of CD5+ B cells. Approximately 8–10% of CLL patients have a first degree relative with CLL, indicating that genetic factors can contribute to disease susceptibility. Genome wide association (GWA) studies have identified 16 “common variants,” single-nucleotide polymorphisms (SNPs) with a population prevalence of >5%, that confer risk for CLL. Among patients with CLL, the clinical course can be highly heterogeneous. Studies have defined disease-characteristics that vary among patients that can be used as markers to help predict clinical outcome. African American (AA) CLL patients have a poorer overall survival than Caucasians. However, there is little information on whether there are distinctive, ethnic-associated disease-characteristics that contribute to differences in clinical outcome. Moreover, studies of the genetics of CLL have involved primarily Caucasian patients. For these reasons, we examined for ethnic-related differences in the distribution and prevalence of CLL-associated SNPs and adverse disease-associated characteristics among AA with CLL relative to those of Caucasian patients with this disease. Methods:The clinical and biologic characteristics of 43 AA CLL patients ascertained at Duke University and the Durham VA Medical Center were tabulated and compared to Caucasian CLL patients at the same centers. Fifteen SNPs were genotyped in this “discovery” cohort of 43 AA CLL patients using TaqMan SNP genotyping assays. As a “validation” cohort, 70 AA CLL patients ascertained by the CLL Research Consortium (CRC) were assayed using the same platform. Three control groups were considered in analysis: (1) previously published Caucasian CLL patients, (2) control AA genotypes reported in the HapMap database and (3) control AA with no history of malignancy from other GWA studies. The 3' untranslated region of CPEB1 was sequenced in AA CLL patients using conventional Sanger sequencing. Results:Among the Duke/Durham VA CLL patients, no significant differences were observed in age, WBC count, platelet count, or hemoglobin at diagnosis; lymphocyte doubling time; Rai stage; ZAP70 expression; or CD38 expression between AA and Caucasian patients. AA had a larger proportion of trisomy 12 and fewer 13q.14 deletions than Caucasians: 40.0% of AA had trisomy 12 and 15.0% had del 13q, compared to 14.6% and 40.7% of Caucasians, respectively. IGHV mutation status also varied between races, with 62.2% of AA having unmutated IGHV, compared to 38.4% of Caucasians. Disparities in clinical outcomes were similar to that reported in the SEER database: overall survival was 8.8 years in AA patients and 17.8 years in Caucasians, and time to first treatment was 2.8 years among AAs and 4.5 years for Caucasians. Risk allele frequencies among 15 genotyped SNPs showed that 14 SNPs had risk allele frequencies that statistically differed between AA patients and Caucasian CLL patients. In 9 of 14 SNPs, the risk allele was less common in AA than in Caucasians but similar to that AA controls. In the other 5 SNPs, the risk allele was more common in AA CLL than Caucasian CLL, and similar to that of AA controls in 4 of the SNPs. A single SNP, rs783540 (CPEB1) was found to have an increased frequency in AA patients with CLL when compared to both Caucasian CLL and control AA. As an exploratory analysis to identify possible pathogenic variants, the 3' UTR of CPEB1 was sequenced as there are no common non-synonymous SNPs in CPEB1. Preliminary review of the sequencing data revealed that a G insertion SNP (rs34816185) that alters a predicted miRNA binding site is in linkage disequilibrium with rs783540 (D'= 0.978). Conclusions:Most SNPs associated with CLL risk are less frequent in AA than in Caucasian CLL patients. However, rs783540 (intron 2, CPEB1) risk allele was more frequent in AA CLL than that previously reported in Caucasian CLL or AA controls. Initial data suggests that rs783540 is linked to a SNP in the 3' UTR of CPEB1, which may have functional significance. Studies to better delineate the functional and clinical implications of these germline variants are underway. Our data provide the first evidence of differential genetic risk as a determinant of CLL biology among different ethnic groups. Disclosures:No relevant conflicts of interest to declare.

Differences in Candidate Gene Association between European Ancestry and African American Asthmatic Children

BackgroundCandidate gene case-control studies have identified several single nucleotide polymorphisms (SNPs) that are associated with asthma susceptibility. Most of these studies have been restricted to evaluations of specific SNPs within a single gene and within populations from European ancestry. Recently, there is increasing interest in understanding racial differences in genetic risk associated with childhood asthma. Our aim was to compare association patterns of asthma candidate genes between children of European and African ancestry.Methodology/Principal FindingsUsing a custom-designed Illumina SNP array, we genotyped 1,485 children within the Greater Cincinnati Pediatric Clinic Repository and Cincinnati Genomic Control Cohort for 259 SNPs in 28 genes and evaluated their associations with asthma. We identified 14 SNPs located in 6 genes that were significantly associated (p-values <0.05) with childhood asthma in African Americans. Among Caucasians, 13 SNPs in 5 genes were associated with childhood asthma. Two SNPs in IL4 were associated with asthma in both races (p-values <0.05). Gene-gene interaction studies identified race specific sets of genes that best discriminate between asthmatic children and non-allergic controls.Conclusions/SignificanceWe identified IL4 as having a role in asthma susceptibility in both African American and Caucasian children. However, while IL4 SNPs were associated with asthma in asthmatic children with European and African ancestry, the relative contributions of the most replicated asthma-associated SNPs varied by ancestry. These data provides valuable insights into the pathways that may predispose to asthma in individuals with European vs. African ancestry.