Population-based Genetic Association Studies Research Articles

Investigation of Genetic Alterations Associated With Interval Breast Cancer

Breast cancers (BCs) diagnosed between 2 screening examinations are called interval cancers (ICs), and they have worse clinicopathological characteristics and poorer prognosis than screen-detected cancers (SDCs). However, the association of rare germline genetic variants with IC have not been studied. To evaluate whether rare germline deleterious protein-truncating variants (PTVs) can be applied to discriminate between IC and SDC while considering mammographic density. This population-based genetic association study was based on women aged 40 to 76 years who were attending mammographic screening in Sweden. All women with a diagnosis of BC between January 2001 and January 2016 were included, together with age-matched controls. Patients with BC were followed up for survival until 2021. Statistical analysis was performed from September 2021 to December 2022. Germline PTVs in 34 BC susceptibility genes as analyzed by targeted sequencing. Odds ratios (ORs) were used to compare IC with SDC using logistic regression. Hazard ratios were used to investigate BC-specific survival using Cox regression. All 4121 patients with BC (IC, n = 1229; SDC, n = 2892) were female, with a mean (SD) age of 55.5 (7.1) years. There were 5631 age-matched controls. The PTVs of the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes were more common in patients with IC compared with SDC (OR, 1.48; 95% CI, 1.06-2.05). This association was primarily influenced by BRCA1/2 and PALB2 variants. A family history of BC together with PTVs of any of these genes synergistically increased the probability of receiving a diagnosis of IC rather than SDC (OR, 3.95; 95% CI, 1.97-7.92). Furthermore, 10-year BC-specific survival revealed that if a patient received a diagnosis of an IC, carriers of PTVs in any of these 5 genes had significantly worse survival compared with patients not carrying any of them (hazard ratio, 2.04; 95% CI, 1.06-3.92). All of these associations were further pronounced in a subset of patients with IC who had a low mammographic density at prior screening examination. The results of this study may be helpful in future optimizations of screening programs that aim to lower mortality as well as the clinical treatment of patients with BC.

Population stratification correction using Bayesian shrinkage priors for genetic association studies.

Population stratification (PS) is a major source of confounding in population-based genetic association studies of quantitative traits. Principal component regression (PCR) and linear mixed model (LMM) are two commonly used approaches to account for PS in association studies. Previous studies have shown that LMM can be interpreted as including all principal components (PCs) as random-effect covariates. However, including all PCs in LMM may dilute the influence of relevant PCs in some scenarios, while including only a few preselected PCs in PCR may fail to fully capture the genetic diversity. To address these shortcomings, we introduce Bayestrat-a method to detect associated variants with PS correction under the Bayesian LASSO framework. To adjust for PS, Bayestrat accommodates a large number of PCs and utilizes appropriate shrinkage priors to shrink the effects of nonassociated PCs. Simulation results show that Bayestrat consistently controls type I error rates and achieves higher power compared to its non-shrinkage counterparts, especially when the number of PCs included in the model is large. As a demonstration of the utility of Bayestrat, we apply it to the Multi-Ethnic Study of Atherosclerosis (MESA). Variants and genes associated with serum triglyceride or HDL cholesterol are identified in our analyses. The automatic and self-selection features of Bayestrat make it particularly suited in situations with complex underlying PS scenarios, where it is unknown a priori which PCs are potential confounders, yet the number that needs to be considered could be large in order to fully account for PS.

Association of Polymorphisms in ZFHX1B and PAX6 With Anisometropia in Chinese Children: The Hong Kong Children Eye Genetics Study.

To identify gene variants associated with anisometropia development in children. This is a population-based, cross-sectional, and longitudinal genetic association study involving 1057 children aged 6 to 10 years with both baseline and 3-year follow-up data. Six single nucleotide polymorphisms (SNPs), ZC3H11B rs4373767, ZFHX1B rs13382811, KCNQ5 rs7744813, SNTB1 rs7839488, PAX6 rs644242, and GJD2 rs524952 were analyzed in all children. Anisometropia was defined by an interocular difference in SE of ≥1 diopter (D) (Aniso-SE) and an interocular difference in axial length (AL) of ≥0.3 mm (Aniso-AL), respectively. Genetic associations of individual SNPs and joint SNP effects were analyzed. ZFHX1B rs13382811 was associated nominally with Aniso-AL (odds ratio [OR], 1.66; P = 0.003) at baseline. At 3 years, rs13382811 was significantly associated with Aniso-AL (OR, 1.49; P = 0.001) and became nominally associated with Aniso-SE (OR, 1.40; P = 0.01). In addition, PAX6 rs644242 was significantly associated with Aniso-AL at 3 years (OR, 1.45; P = 0.002). At the 3-year follow-up, PAX6 rs644242 was associated significantly with Aniso-AL development (OR, 1.61; P = 0.0003) and nominally with Aniso-SE development (P = 0.03) in children who were not anisometropic at baseline, whereas ZFHX1B rs13382811 was associated nominally with Aniso-AL development (P = 0.02). An additive SNP analysis indicated children carrying the risk allele T of ZFHX1B rs13382811 and allele A of PAX6 rs644242 might have a 4.33- and 6.90-fold of increased risk of Aniso-SE and Aniso-AL development by 3 years, respectively. This study identified two susceptible gene variants, ZFHX1B rs13382811 and PAX6 rs644242, for anisometropia development in Hong Kong Chinese children, implicating their role in imbalanced refractive change and axial elongation between both eyes.

Associated and intermediate factors between genetic variants of the dopaminergic D2 receptor gene and harmful alcohol use in young adults.

Dopamine receptor D2 (DRD2) and ankyrin repeat and kinase domain-containing protein 1 (ANKK1) genes have received considerable attention for their involvement in alcohol use disorder (AUD), but many questions remain on their exact role. We conducted a population-based case-control and genetic association study in a large sample of young adults. Our aim was to assess the association between DRD2 and ANKK1 single nucleotide polymorphisms (SNPs) and harmful alcohol use, disentangling associated and possible intermediate factors. A total of 1841 college students from the French region Champagne-Ardennes, aged between 18 and 21 years and who reported at least one lifetime alcohol consumption, were included in this study. Allele frequencies were analysed according to harmful alcohol use (assessed through the Alcohol Use Disorder Identification Test [AUDIT] questionnaire). Different substance use disorders, including nicotine and cannabis dependences, were also assessed through questionnaires, as was a list of potential associated factors (e.g., major depressive episode, conduct disorder, attention-deficit/hyperactivity disorder [ADHD], school failure, sugar consumption, sexual trauma, parents' use of alcohol, tobacco or cannabis). We found that DRD2 rs1800498 was associated with harmful alcohol use. Many factors were detected, but a global path analysis revealed that DRD2 rs1800498 had a significant direct effect on harmful alcohol use and that early age at first alcohol consumption and depressive symptoms moderated this effect. This study suggests an interplay between harmful alcohol use, DRD2 genotypes and other risk factors that, with a full understanding, could be useful for preventive purposes.

Deep learning predicts DNA methylation regulatory variants in the human brain and elucidates the genetics of psychiatric disorders

There is growing evidence for the role of DNA methylation (DNAm) quantitative trait loci (mQTLs) in the genetics of complex traits, including psychiatric disorders. However, due to extensive linkage disequilibrium (LD) of the genome, it is challenging to identify causal genetic variations that drive DNAm levels by population-based genetic association studies. This limits the utility of mQTLs for fine-mapping risk loci underlying psychiatric disorders identified by genome-wide association studies (GWAS). Here we present INTERACT, a deep learning model that integrates convolutional neural networks with transformer, to predict effects of genetic variations on DNAm levels at CpG sites in the human brain. We show that INTERACT-derived DNAm regulatory variants are not confounded by LD, are concentrated in regulatory genomic regions in the human brain, and are convergent with mQTL evidence from genetic association analysis. We further demonstrate that predicted DNAm regulatory variants are enriched for heritability of brain-related traits and improve polygenic risk prediction for schizophrenia across diverse ancestry samples. Finally, we applied predicted DNAm regulatory variants for fine-mapping schizophrenia GWAS risk loci to identify potential novel risk genes. Our study shows the power of a deep learning approach to identify functional regulatory variants that may elucidate the genetic basis of complex traits.

Incorporating family disease history and controlling case-control imbalance for population-based genetic association studies.

ABSTRACTMotivationIn the genome-wide association analysis of population-based biobanks, most diseases have low prevalence, which results in low detection power. One approach to tackle the problem is using family disease history, yet existing methods are unable to address type I error inflation induced by increased correlation of phenotypes among closely related samples, as well as unbalanced phenotypic distribution.ResultsWe propose a new method for genetic association test with family disease history, mixed-model-based Test with Adjusted Phenotype and Empirical saddlepoint approximation, which controls for increased phenotype correlation by adopting a two-variance-component mixed model, accounts for case–control imbalance by using empirical saddlepoint approximation, and is flexible to incorporate any existing adjusted phenotypes, such as phenotypes from the LT-FH method. We show through simulation studies and analysis of UK Biobank data of white British samples and the Korean Genome and Epidemiology Study of Korean samples that the proposed method is robust and yields better calibration compared to existing methods while gaining power for detection of variant–phenotype associations.Availability and implementationThe summary statistics and code generated in this study are available at https://github.com/styvon/TAPE.Supplementary information Supplementary data are available at Bioinformatics online.

Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci

ObjectivesNearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly...

Genetic Risk Score Is Associated with Vertical Cup-to-Disc Ratio and Improves Prediction of Primary Open-Angle Glaucoma in Latinos

Genome-wide association studies have identified multiple genetic variants associated with vertical cup-to-disc ratio (VCDR). Genetic risk scores (GRS) examine the aggregate genetic effect of individual variants on a trait by combining these separate genetic variants into a single measure. The purpose of this study was to construct GRS for VCDR and to determine whether the GRS are associated with VCDR and whether the GRS increase the discriminatory ability for primary open-angle glaucoma (POAG) in a Latino population. Population-based genetic association study. A total of 4018 Latino participants recruited from Los Angeles. Weighted and unweighted GRS were constructed using 68 previously reported VCDR single nucleotide polymorphisms (SNPs), as well as SNPs from our own genome-wide association data. Linear and logistic regression analyses examined the associations of GRS with VCDR and POAG, respectively. To evaluate the discriminatory ability of the GRS for POAG, we conducted receiver operating characteristic (ROC) analyses. The relationship between GRS and VCDR in Latinos. The GRS were associated significantly with VCDR (P < 0.0001), after adjusting for age, gender, central corneal thickness, intraocular pressure, and education. The weighted GRS explained an additional 2.74% of the variation in VCDR. Adding the weighted GRS derived from previously reported SNPs resulted in a moderate improvement in the discriminatory ability for POAG during ROC analyses, yielding an area under the ROC curve (AUC) of 0.735 (95% CI, 0.701-0.768). When our own SNPs were used, the AUC increased significantly to 0.809 (95% CI, 0.781-0.837; P < 0.0001). We obtained similar results for the unweighted GRS. To our knowledge, we identified a novel association between GRS and VCDR and its improvement in the discriminatory ability of POAG in a Latino population.

African Ancestry Is Associated with Higher Intraocular Pressure in Latinos

Intraocular pressure (IOP) is a major risk factor, as well as the only modifiable risk factor, for glaucoma. Racial differences have been observed in IOP measurements with individuals of African descent experiencing the highest IOP when compared with other ethnic groups. The purpose of this study was to examine the relationship between genetic ancestry and IOP in Latinos. Population-based genetic association study. A total of 3541 participants recruited from the Los Angeles Latino Eye Study. Study participants were genotyped using the Illumina OmniExpress BeadChip (∼730K markers). We used STRUCTURE to estimate individual genetic ancestry. Simple and multiple linear regression, as well as quantile regression, analyses were performed to investigate the relationship between genetic ancestry and IOP. The relationship between genetic ancestry and IOP in Latinos. African ancestry was significantly associated with higher IOP in Latinos in our simple linear regression analysis (P= 0.002). After adjusting for age, gender, body mass index, systolic blood pressure, central corneal thickness, and type 2 diabetes, this association remained significant (P= 0.0005). The main association was modified by a significant interaction between African ancestry and hypertension (P= 0.037), with hypertensive individuals experiencing a greater increase in IOP with increasing African ancestry. To our knowledge, we demonstrate for the first time that African ancestry and its interaction with hypertension are associated with higher IOP in Latinos.

The Essentiality of Reporting Hardy-Weinberg Equilibrium Calculations in Population-Based Genetic Association Studies.

Population-based genetic association studies have proven to be a powerful tool in identifying genes implicated in many complex human diseases that have a huge impact on public health. An essential quality control step in such studies is to undertake Hardy-Weinberg equilibrium (HWE) calculations. Deviations from HWE in the control group may reflect important problems including selection bias, population stratification and genotyping errors. If HWE is violated, the inferences of these studies may thus be biased. We therefore aimed to examine the extent to which HWE calculations are reported in genetic association studies published in Cell Journal(Yakhteh)(Cell J). Using keywords pertaining to genetic association studies, eleven relevant articles were identified of which ten provided full genotypic data. The genotype distribution of 16 single nucleotide polymorphisms (SNPs) was re-analyzed for HWE by using three different methods where appropriate. HWE was not reported in 60% of all articles investigated. Among those reporting, only one article provided calculations correctly and in detail. Therefore, 90% of articles analyzed failed to provide sufficient HWE data. Interestingly, three articles had significant HWE deviation in their control groups of which one highly deviated from HWE expectations (P= 9.8×10(-12)). We thus show that HWE calculations are under-reported in genetic association studies published in this journal. Furthermore, the conclusions of the three studies showing significant HWE in their control groups should be treated cautiously as they may be potentially misleading. We therefore recommend that reporting of detailed HWE calculations should become mandatory for such studies in the future.

Neurogenetics in Peru: clinical, scientific and ethical perspectives.

Neurogenetics, the science that studies the genetic basis of the development and function of the nervous system, is a discipline of recent development in Peru, an emerging Latin American country. Herein, we review the clinical, scientific and ethical aspects regarding the development of this discipline, starting with the first molecular diagnosis of neurogenetic diseases, to family and population-based genetic association studies. Neurogenetics in Peru aims to better explain the epidemiology of monogenic and complex neurodegenerative disorders that will help in implementing public health policies for these disorders. The characterization of Peru and its health system, legal issues regarding rare diseases and the historical milestones in neurogenetics are also discussed.

Genetic Structure of Cartagena de Indias Population Using Hypervariable Markers of Y Chromosome

Ethnicity has been associated with the incidence of diseases and consequently it is a cornerstone in medical genetic studies. It is mainly important in admixture populations, where the population stratification can produce spurious results that lead to erroneous conclusions. Consequently, population stratification has become one of the most important confounding factors in population-based genetic association studies, especially in Latino populations. Cartagena de Indias is a cosmopolitan city with dissimilar ancestry proportions due to recent miscegenation. This population mainly exhibits African and Amerindian matrilineal ancestries. Nevertheless, important asymmetries in the paternal genetic history related to the complex patterns of migration in the colonial period increase the male genetic diversity in this population. As a result of this recent admixture, population stratification has arisen, where each subpopulation is not equally represented. Consequently, the allele differences between cases and controls could be related with different frequencies among different population strata rather than the association of the genes with the disease. In order to define the patrilineal substructure of the Cartagena’s population, a total of 130 unrelated men were ancestrally studied using 15 Y-STR loci routinely employed in anthropological, forensic and population genetics. Our results show that Cartagena is an admixture population consisting of European (80%), Amerindian (10%) and African ancestries (10%), which are represented by haplogroups R1b and I2a (xI2a1), Q-M242/Q-M3, and E1b1a/E1b1b, respectively. Complex genetic patterns found in Cartagena’s population emphasize the importance to know the genetic variation in order to diminish the inconsistence for future genetic association studies. In addition, our findings illustrate the complex genetic background of Cartagena population and reinforce the need to encompass more geographic regions to generate more robust data for anthropological and forensic applications.

Imaging genetics — towards discovery neuroscience

Imaging genetics is an emerging field aimed at identifying and characterizing genetic variants that influence measures derived from anatomical or functional brain images, which are in turn related to brain‐related illnesses or fundamental cognitive, emotional and behavioral processes, and are affected by environmental factors. Here we review the recent evolution of statistical approaches and outstanding challenges in imaging genetics, with a focus on population‐based imaging genetic association studies. We show the trend in imaging genetics from candidate approaches to pure discovery science, and from univariate to multivariate analyses. We also discuss future directions and prospects of imaging genetics for ultimately helping understand the genetic and environmental underpinnings of various neuropsychiatric disorders and turning basic science into clinical strategies.

Statistical genetics with application to population-based study design: a primer for clinicians

With the completion of the entire human genome sequence and remarkable advances in genotyping technologies, there has been an increased interest in the application of genetics and genomics in biomedical research over the last decade. Large-scale population-based genetic association studies have now become routine and their application to several multifactorial diseases such as cardiovascular disorders has led to the identification of a number of novel susceptibility genes. However, to be able to interpret results from such studies, clinicians need to have a basic understanding of unique concepts and issues related to this fast-moving area of research. In this primer, we provide a broad overview of design, analysis, and methodological issues with a focus on population-based study design.

Association of AMP-Activated Protein Kinase with Risk and Progression of Non–Hodgkin Lymphoma

Metabolic dysregulation has been identified as an "emerging hallmark" of cancer. The heterotrimeric AMP-activated protein kinase (AMPK) complex is a central regulator of the metabolic system and an important component of the mTOR pathway and the p53 axis, making it uniquely positioned to influence carcinogenesis through its canonical functions in the metabolic arena, as well as through more traditional mechanisms such as regulation of apoptosis and angiogenesis. We conducted a population-based genetic association study to examine the impact of mutations in AMPK subunit genes on risk of non-Hodgkin lymphoma (NHL). We also analyzed public microarray data to determine the expression of AMPK in NHL cells and to assess the influence of AMPK expression on overall survival in patients with NHL. We identified an AMPK subunit haplotype, which was significantly associated with NHL [OR, 5.44, 95% confidence interval (CI), 2.15-13.75] in women with no family history of cancer. Haplotypes in two subunits, PRKAA2 and PRKAG3, were nominally associated with the follicular and diffuse large B-cell lymphoma histologic subtypes, respectively, although these associations did not retain statistical significance after correction for multiple comparisons. Further, both of these subunits were differentially expressed (P < 0.05) in one or more lymphoma cell type, and higher expression of two versions of the AMPK-β subunit was significantly associated with increased 5-year survival among patients with NHL (P = 0.001 and P = 0.021). These results provide evidence for AMPK involvement in the pathogenesis and progression of NHL. These findings may lead to a novel area of research into NHL treatment and chemoprevention.

The association between apolipoprotein E gene polymorphisms and essential hypertension: a meta-analysis of 45 studies including 13 940 cases and 16 364 controls

The apolipoprotein E single-nucleotide polymorphisms are among the potential candidate genes that may serve as modulators in susceptibility to essential hypertension. In an effort to clarify earlier inconclusive results, we performed a meta-analysis of population-based case-control genetic association studies. Random-effects methods were applied on summary data in order to combine the results of the individual studies. We identified in total 45 studies, including 13 940 hypertensive cases and 16 364 controls. The contrast of E4 carriers versus non-carriers yielded an overall odds ratio (OR) of 1.16 (95% confidence interval (CI): 1.02, 1.31), whereas the contrast of E4 allele versus the others in a subtotal of 6617 cases and 7330 controls, yielded an OR of 1.39 (95% CI: 1.12, 1.72). There was moderate evidence of publication bias in both contrasts, which was eliminated after excluding studies not in Hardy-Weinberg equilibrium. Subgroup analyses revealed that significant estimates arose from studies on Asian populations, as opposed to the Caucasian ones. Furthermore, no evidence of publication bias was demonstrated in the comparisons within this subgroup. Our results are consistent with recent meta-analyses but show that the association is weaker than that has been previously demonstrated. Further studies are needed in order to fully address questions about the etiological mechanism of the particular association, as well as to study the effect in populations of African descent.

Abstract 1652: Targetome profiling and genetic association analyses implicate miR-202 in follicular lymphomagenesis

Abstract Complex etiologic heterogeneity among non-Hodgkin's lymphoma (NHL) subtypes has made it difficult to identify risk factors for this disease. However, recent genetic association analyses, including two genome-wide association studies, suggest that genetic susceptibility to NHL may be strongest for the follicular lymphoma subtype. As recent studies have demonstrated that microRNAs (miRNAs) may be important in the etiology of many cancer types, including NHL, we performed a population-based genetic association study which identified a polymorphism in the precursor of miR-202 that is strongly associated with follicular lymphoma risk (rs12355840 in miR-202: PTREND = 0.006). An in vitro functional genetics assay demonstrated that the polymorphism is biologically active, and operates by altering the processing efficiency of the miR-202 precursor to the mature effector miRNA species. A ribonucleoprotein immunoprecipitation-microarray (RIP-Chip) assay, performed with an anti-AGO2 antibody followed by a whole-genome array, was used to characterize the miR-202 targetome, and selected targets were confirmed using a 3′UTR luciferase assay. Among the identified targets were several transcripts with relevance for tumorigenesis, including the miRNA biogenesis gene DICER1 and the lymphoma-associated cell cycle regulator and proto-oncogene SKP2. Both of these genes have been shown to be upregulated in lymphomas, which is consistent with our data, which show that the miR-202 risk allele is associated with diminished mature miR-202 levels in vitro. Taken together, these findings suggest that rs12355840 may represent a novel risk biomarker for follicular lymphoma, and implicate miR-202 in follicular lymphomagenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1652. doi:1538-7445.AM2012-1652

EPHA2 Polymorphisms and Age-Related Cataract in India

ObjectiveWe investigated whether previously reported single nucleotide polymorphisms (SNPs) of EPHA2 in European studies are associated with cataract in India.MethodsWe carried out a population-based genetic association study. We enumerated randomly sampled villages in two areas of north and south India to identify people aged 40 and over. Participants attended a clinical examination including lens photography and provided a blood sample for genotyping. Lens images were graded by the Lens Opacification Classification System (LOCS III). Cataract was defined as a LOCS III grade of nuclear ≥4, cortical ≥3, posterior sub-capsular (PSC) ≥2, or dense opacities or aphakia/pseudophakia in either eye. We genotyped SNPs rs3754334, rs7543472 and rs11260867 on genomic DNA extracted from peripheral blood leukocytes using TaqMan assays in an ABI 7900 real-time PCR. We used logistic regression with robust standard errors to examine the association between cataract and the EPHA2 SNPs, adjusting for age, sex and location.Results7418 participants had data on at least one of the SNPs investigated. Genotype frequencies of controls were in Hardy-Weinberg Equilibrium (p>0.05). There was no association of rs3754334 with cataract or type of cataract. Minor allele homozygous genotypes of rs7543472 and rs11260867 compared to the major homozygote genotype were associated with cortical cataract, Odds ratio (OR) = 1.8, 95% Confidence Interval (CI) (1.1, 3.1) p = 0.03 and 2.9 (1.2, 7.1) p = 0.01 respectively, and with PSC cataract, OR = 1.5 (1.1, 2.2) p = 0.02 and 1.8 (0.9, 3.6) p = 0.07 respectively. There was no consistent association of SNPs with nuclear cataract or a combined variable of any type of cataract including operated cataract.ConclusionsOur results in the Indian population agree with previous studies of the association of EPHA2 variants with cortical cataracts. We report new findings for the association with PSC which is particularly prevalent in Indians.

Random forests analysis: A modern statistical method for screening in high-dimensional studies and its application in a population-based genetic association study

Random forests analysis: A modern statistical method for screening in high-dimensional studies and its application in a population-based genetic association study

Exogenous Visual Orienting Is Associated with Specific Neurotransmitter Genetic Markers: A Population-Based Genetic Association Study

BackgroundCurrently, there is a sense that the spatial orienting of attention is related to genotypic variations in cholinergic genes but not to variations in dopaminergic genes. However, reexamination of associations with both cholinergic and dopaminergic genes is warranted because previous studies used endogenous rather than exogenous cues and costs and benefits were not analyzed separately. Examining costs (increases in response time following an invalid pre-cue) and benefits (decreases in response time following a valid pre-cue) separately could be important if dopaminergic genes (implicated in disorders such as attention deficit disorder) independently influence the different processes of orienting (e.g., disengage, move, engage).Methodology/Principal FindingsWe tested normal subjects (N = 161) between 18 and 61 years. Participants completed a computer task in which pre-cues preceded the presence of a target. Subjects responded (with a key press) to the location of the target (right versus left of fixation). The cues could be valid (i.e., appear where the target would appear) or invalid (appear contralateral to where the target would appear). DNA sequencing assays were performed on buccal cells to genotype known genetic markers and these were examined for association with task scores. Here we show significant associations between visual orienting and genetic markers (on COMT, DAT1, and APOE; R2s from 4% to 9%).Conclusions/SignificanceOne measure in particular – the response time cost of a single dim, invalid cue – was associated with dopaminergic markers on COMT and DAT1. Additionally, variations of APOE genotypes based on the ε2/ε3/ε4 alleles were also associated with response time differences produced by simultaneous cues with unequal luminances. We conclude that individual differences in visual orienting are related to several dopaminergic markers as well as to a cholinergic marker. These results challenge the view that orienting is not associated with genotypic variation in dopaminergic genes.