Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits.

Anxiety-related personality traits, such as NEO neuroticism and TCI/TPQ harm avoidance, have been shown to have significant genetic components. To date, however, no specific genetic variants that contribute to these traits have been conclusively identified. At least 26 studies have investigated a putative association between a functional serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. The results of these studies have been inconsistent with some studies finding evidence for an association, and others not. We performed a meta-analysis of all applicable studies investigating this association. In the overall analysis (N = 5,629 subjects), we found suggestive evidence for an association between the 5-HTTLPR short allele (s) and increased anxiety-related personality trait scores (P = 0.087). However, we also found strong evidence for heterogeneity. This heterogeneity is largely explained by substantial variation between the studies in the inventory used. When the analysis was stratified by inventory type, there was a significant association between 5-HTTLPR and NEO neuroticism (P = 0.000016), a non-significant association between 5-HTTLPR and TCI/TPQ harm avoidance (P = 0.166), and no association between 5-HTTLPR and other anxiety-related personality traits (P = 0.944). There was no evidence that these results were either due to publication bias or accounted for by any one single study. We conclude that there is a strong association between the serotonin transporter promoter variant and neuroticism as measured in the NEO personality inventory and that non-replications are largely due to small sample size and the use of different inventories.     

Genetic covariation of neuroticism with monoamine oxidase activity and smoking

Variation in the personality trait of neuroticism is known to be affected by genetic influences, but despite a number of association studies, the genes involved have not yet been characterized. In a recent study of platelet monoamine oxidase in 1,551 twin subjects, we found a significant association between monoamine oxidase activity and scores on the Eysenck Personality Questionnaire neuroticism scale. Further analyses presented here indicate that both neuroticism and monoamine oxidase activity are associated with variation in smoking habits, and that adjusting for the effect of smoking strengthens the association between MAO and neuroticism. Analysis of the genetic and environmental sources of covariation between neuroticism, smoking, and monoamine oxidase activity show that approximately 8% of the genetic variance in neuroticism is due to the same additive genetic effects that contribute to variation in monoamine oxidase activity, suggesting that variation in neuroticism is associated in part with aspects of serotonin metabolism. © 2001 Wiley‐Liss, Inc.     

Genetic covariation of neuroticism with monoamine oxidase activity and smoking.

Variation in the personality trait of neuroticism is known to be affected by genetic influences, but despite a number of association studies, the genes involved have not yet been characterized. In a recent study of platelet monoamine oxidase in 1,551 twin subjects, we found a significant association between monoamine oxidase activity and scores on the Eysenck Personality Questionnaire neuroticism scale. Further analyses presented here indicate that both neuroticism and monoamine oxidase activity are associated with variation in smoking habits, and that adjusting for the effect of smoking strengthens the association between MAO and neuroticism. Analysis of the genetic and environmental sources of covariation between neuroticism, smoking, and monoamine oxidase activity show that approximately 8% of the genetic variance in neuroticism is due to the same additive genetic effects that contribute to variation in monoamine oxidase activity, suggesting that variation in neuroticism is associated in part with aspects of serotonin metabolism.     

Broad bandwidth or high fidelity? Evidence from the structure of genetic and environmental effects on the facets of the five factor model

The Five Factor Model of personality is well-established at the phenotypic level, but much less is known about the coherence of the genetic and environmental influences within each personality domain. Univariate behavioral genetic analyses have consistently found the influence of additive genes and nonshared environment on multiple personality facets, but the extent to which genetic and environmental influences on specific facets reflect more general influences on higher order factors is less clear. We applied a multivariate quantitative-genetic approach to scores on the CPI-Big Five facets for 490 monozygotic and 317 dizygotic twins who took part in the National Merit Twin Study. Our results revealed a complex genetic structure for facets composing all five factors, with both domain-general and facet-specific genetic and environmental influences. For three of the Big Five domains, models that required common genetic and environmental influences on each facet to occur by way of effects on a higher order trait did not fit as well as models allowing for common genetic and environmental effects to act directly on the facets. These results add to the growing body of literature indicating that important variation in personality occurs at the facet level which may be overshadowed by aggregating to the trait level. Research at the facet level, rather than the factor level, is likely to have pragmatic advantages in future research on the genetics of personality.     

Identification of cis-regulatory variation influencing protein abundance levels in human plasma

Proteins are central to almost all cellular processes, and dysregulation of expression and function is associated with a range of disorders. A number of studies in human have recently shown that genetic factors significantly contribute gene expression variation. In contrast, very little is known about the genetic basis of variation in protein abundance in man. Here, we assayed the abundance levels of proteins in plasma from 96 elderly Europeans using a new aptamer-based proteomic technology and performed genome-wide local (cis-) regulatory association analysis to identify protein quantitative trait loci (pQTL). We detected robust cis-associations for 60 proteins at a false discovery rate of 5%. The most highly significant single nucleotide polymorphism detected was rs7021589 (false discovery rate, 2.5 × 10(-12)), mapped within the gene coding sequence of Tenascin C (TNC). Importantly, we identified evidence of cis-regulatory variation for 20 previously disease-associated genes encoding protein, including variants with strong evidence of disease association show significant association with protein abundance levels. These results demonstrate that common genetic variants contribute to the differences in protein abundance levels in human plasma. Identification of pQTLs will significantly enhance our ability to discover and comprehend the biological and functional consequences of loci identified from genome-wide association study of complex traits. This is the first large-scale genetic association study of proteins in plasma measured using a novel, highly multiplexed slow off-rate modified aptamer (SOMAmer) proteomic platform.     

Genetic architecture of quantitative traits in mice,flies, and humans

We compare and contrast the genetic architecture of quantitative phenotypes in two genetically well-characterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, with that found in our own species from recent successes in genome-wide association studies. We show that the current model of large numbers of loci, each of small effect, is true for all species examined, and that discrepancies can be largely explained by differences in the experimental designs used. We argue that the distribution of effect size of common variants is the same for all phenotypes regardless of species, and we discuss the importance of epistasis, pleiotropy, and gene by environment interactions. Despite substantial advances in mapping quantitative trait loci, the identification of the quantitative trait genes and ultimately the sequence variants has proved more difficult, so that our information on the molecular basis of quantitative variation remains limited. Nevertheless, available data indicate that many variants lie outside genes, presumably in regulatory regions of the genome, where they act by altering gene expression. As yet there are very few instances where homologous quantitative trait loci, or quantitative trait genes, have been identified in multiple species, but the availability of high-resolution mapping data will soon make it possible to test the degree of overlap between species.Recent successes in mapping quantitative trait loci (QTLs) that contribute to phenotypic variation in humans and model organisms make it possible to address important questions about the genetic architecture of quantitative phenotypes, such as the likely number of loci, their mode of genetic action, and interaction with each other and with the environment. An understanding of the genetic architecture of quantitative traits is not only important in its own right, it will also inform studies that seek to proceed to the identification of the quantitative trait genes (QTGs) and the quantitative trait nucleotide (QTN) variants, the functional changes in DNA sequence that contribute to trait variation.In this work we use examples from two genetically well-characterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, to discuss how an understanding of the genetic architecture of quantitative phenotypes in model organisms informs mapping experiments in human genetics. In our discussion of the latter, we draw upon the recent successful application of genome-wide association studies (GWAS) to both quantitative phenotypes (such as height and weight) and disease phenotypes (assuming that the genetic architecture of common disease is similar, if not identical, to that of quantitative phenotypes).Genetic architecture has been the subject of a number of recent reviews, most of which deal with information from a single model organism (Mackay 2004) or review a small number of phenotypes (Kendler and Greenspan 2006). Here, our purpose is different. We tackle three related questions. (1) How much does genetic architecture differ between species? (2) How much does genetic architecture vary between phenotypes? (3) Are the same genes involved in the same phenotype in different species? Answers to these questions are important because of the need to identify genes involved in human disease phenotypes and to determine how those genes exert their effect. Currently, model organisms such as the fly and the mouse are the resources of choice for functional genetic studies.     

Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: Genome‐wide association study of both common and rare variants

Attention‐deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case–control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM‐IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome‐wide association analyses were performed using PLINK. SNP‐heritability and SNP‐genetic correlations with ADHD in Caucasians were estimated with genome‐wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein–Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome‐wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP‐heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP‐genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology. © 2013 Wiley Periodicals, Inc.     

Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma

Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case-control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case-control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14-1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk.     

Smoothed functional principal component analysis for testing association of the entire allelic spectrum of genetic variation

Fast and cheaper next-generation sequencing technologies will generate unprecedentedly massive and highly dimensional genetic variation data that allow nearly complete evaluation of genetic variation including both common and rare variants. There are two types of association tests: variant-by-variant test and group test. The variant-by-variant test is designed to test the association of common variants, while the group test is suitable to collectively test the association of multiple rare variants. We propose here a smoothed functional principal component analysis (SFPCA) statistic as a general approach for testing association of the entire allelic spectrum of genetic variation (both common and rare variants), which utilizes the merits of both variant-by-variant analysis and group tests. By intensive simulations, we demonstrate that the SFPCA statistic has the correct type 1 error rates and much higher power than the existing methods to detect association of (1) common variants, (2) rare variants, (3) both common and rare variants and (4) variants with opposite directions of effects. To further evaluate its performance, the SFPCA statistic is applied to ANGPTL4 sequence and six continuous phenotypes data from the Dallas Heart Study as an example for testing association of rare variants and a GWAS of schizophrenia data as an example for testing association of common variants. The results show that the SFPCA statistic has much smaller P-values than many existing statistics in both real data analysis examples.     

Power and SNP tagging in whole mitochondrial genome association studies

The application of genetic association studies to detect mitochondrial variants responsible for phenotypic variation has recently been demonstrated. However, the only power estimates currently available are based on the use of mitochondrial haplogroups, which can only tag a small fraction of the common variation in the mitochondrial genome. Here, power estimates are derived for a SNP-based study design for both disease (case-control) and quantitative trait mapping studies. Power is estimated using simulations based on a collection of publicly available mitochondrial sequences of European origin. The power when testing all common mitochondrial SNPs is shown to be equivalent to that when testing only tagging SNPs, despite the relatively high ratio of tagging SNPs to total SNPs resulting from the tagging of all SNPs with a minor allele frequency greater than 1%. The sample size requirements of mitochondrial genome association studies are compared with that of nuclear whole-genome studies. Remarkably, the trade off between the number of tests being performed and the proportion of phenotypic variance explained for a fixed effect size results in approximately equal sample sizes required for both study types, although the per individual cost for the mitochondrial association study is much less. To test the representation of the sequences used in the power simulations, a sample of 3839 individuals from 1037 Australian families was genotyped for 69 tagging SNPs. The strong concordance in allele frequencies and linkage disequilibrium between the European sequences and the Australian sample indicates that the results presented here are transferable across populations of European descent.     

Sleep duration and personality in Croatian twins

The objective of this study was to examine which genetic and environmental influences contribute to individual differences in sleep duration in a sample of Croatian adolescent/early adult twins, as well as to investigate the relationship between personality and sleep duration. Participants included 339 twin pairs (105 monozygotic and 234 dizygotic) aged between 15 and 22 years. They reported on their average sleep duration and personality. The broad heritability estimate (additive and non‐additive genetic influences) for sleep duration was 0.63, while personality estimates ranged between 0.47 and 0.62. Significant negative phenotypic associations with neuroticism and openness were mainly genetically mediated 100 and 80%, respectively. Only 6% of the sleep duration variance was explained by genetic influences shared with neuroticism and openness. In regression analysis, age, gender and five personality traits explained 5% of sleep duration variance, with neuroticism and openness as significant predictors. Comparison of short, moderate and long sleepers showed that participants in the short sleepers group had significantly higher neuroticism scores than groups of moderate and long sleepers, as well as a significantly higher openness score than the group of long sleepers. This indicates that personality traits of neuroticism and openness contribute to the prediction of sleep duration due to overlapping genetic influences that contribute to both these personality traits and sleep duration. However, as phenotypic overlap of personality and sleep duration is relatively weak, heritability of sleep duration is not only related to individual differences in personality traits, so future research needs to examine other phenotypic correlates of sleep duration.     

Common haplotypes in five genes influence genetic variance of LDL and HDL cholesterol in the general population

We studied the association between common haplotypes in six relevant lipid metabolism genes with plasma lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic triglyceride lipase (HL), low-density lipoprotein cholesterol receptor (LDLR), apolipoprotein E (ApoE) and lecithin-cholesterol acyltransferase (LCAT) genes, and studied 732 individuals from 184 German families. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) were similar to those reported in other European and American populations. Haplotypes derived from SNP combinations resulted in more significance and of a higher degree than did single SNPs in the genotype-phenotype association analysis. Reduction of the polygenic variance attributable to haplotypes was estimated using variance components analysis. Under the biometrical genetic model, allelic association of haplotypes was highly significant for HDL, LDL and the LDL/HDL ratio. The residual kinship correlation was reduced accordingly. The ApoE gene had a strong effect on trait variation; however, the other genes also contributed substantially. An epistatic interaction could not be demonstrated in this sample. The data are consistent with the notion that common genetic variants influence common traits.     

Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and personality traits in asymptomatic patients with panic disorder

The serotonin transporter promoter polymorphism (5-HTTLPR) has been investigated regarding its association with neuroticism, which, in its turn, is a personality dimension often found in patients with panic disorder (PD). It has been recently evidenced that the long 5-HTTLPR polymorphism has a genetic variation (Lg), which is related to its lower expression. The objective of this study was to assess the association between the 5-HTTLPR polymorphism in the triallelic system and the neurotic personality traits in patients in PD remission. Sixty-seven Caucasian patients with PD diagnosis according to the DSM-IV-TR assessed with the MINI (mini international neuropsychiatric interview) were included. The MMPI (Minnesota multiphasic personality inventory) was used to assess the personality. The remission of PD symptoms was defined as CGI (clinical global impression) 相似文献   

Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits

Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P?相似文献   

A family-based association study does not support DYX1C1 on 15q21.3 as a candidate gene in developmental dyslexia

We applied a family-based association approach to investigate the role of the DYX1C1 gene on chromosome 15q as a candidate gene for developmental dyslexia (DD) to 158 families containing at least one dyslexic child. We directly sequenced exons 2 and 10 of the DYX1C1 gene and found eight single nucleotide polymorphism (SNPs), three of which (-3G>A, 1249 G>T, 1259 C>G) were suitable for the genetic analyses. We performed single- and multimarker association analyses with DD as a categorical trait by FBAT version 1.4 and TRANSMIT version 2.5.4 programs. Our sample had a power of at least 80% to detect an association between the selected phenotypes and the informative polymorphisms at a significance level of 5%. The results of the categorical analyses did not support the involvement of the DYX1C1 gene variants in this sample of dyslexics and their relatives. Quantitative and multimarker analyses, which provide greater power to detect loci with a minor effect, consistently yielded nonsignificant results. While D1X1C1 is a good candidate gene for DD, we were unable to replicate the original findings between DYX1C1 gene and DD, perhaps due to genetic heterogeneity.     

Allelic variants of the alpha1a adrenoceptor and the promoter region of the alpha2a adrenoceptor and temperament factors.

Human personality traits are partially determined by genes. It has been suggested that the reward-dependence dimension assessed by the Tridimensional Personality Questionnaire (TPQ) is related to the central noradrenergic system. Our population-based association study tested the hypothesis that genetic variants of the adrenoceptor are associated with this personality trait. The alpha1a- and the alpha2a-adrenoceptor genotypes were determined for 198 healthy Han Chinese who had completed the TPQ. We found no significant differences for TPQ personality-factor scores, including reward dependence and its subscales, for subjects showing different adrenoceptor genotypes. Our negative findings suggest that polymorphisms of the alpha1a adrenoceptor and of the promoter region of the alpha2a-adrenoceptor have no major effect on the reward-dependence personality trait as assessed by TPQ.     

Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission and is thought to influence emotion. A 5-HTT-linked polymorphic region (5-HTTLPR) has two common variants, short (s) and long (l). We previously found population and within-family associations between the lower-expressing s allele and neuroticism, a trait related to anxiety, hostility, and depression, on a standard measure (the NEO Personality Inventory, Revised [NEO-PI-R]) in a primarily male population (n=505), and that the s allele was dominant. We investigated this association in a new sample (n=397, 84% female, primarily sib-pairs). The results robustly replicated the 5-HTTLPR neuroticism association, and the dominance of the s allele. Combined data from the two studies (n=902) showed a highly significant association between the s allele and higher NEO Neuroticism both across individuals and within families. Association between genotype and a related measure, Anxiety on the 16PF inventory, was replicated in the new population and within families in the combined sample. Association to another trait, estimated TPQ Harm Avoidance, was not replicated in the new sample but found only within the combined sibship group. Another association found in our original study, between the s allele and lower scores on NEO-PI-R Agreeableness, was also replicated and was more robust in the current and the combined samples. Associations between the functional 5-HTTLPR polymorphism were similar in women and men. These results help to define specific personality features reproducibly associated with 5-HTTLPR genotype. Such associations were strongest for traits defined by the NEO, enhancing the attractiveness of the five-factor personality model in genetic research on complex behavioral dimensions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:202-216, 2000. Published 2000 Wiley-Liss, Inc.     

Borderline personality traits and adult attention‐deficit hyperactivity disorder symptoms: A genetic analysis of comorbidity

Previous research has established the comorbidity of adult Attention‐Deficit Hyperactivity Disorder (ADHD) with different personality disorders including Borderline Personality Disorder (BPD). The association between adult ADHD and BPD has primarily been investigated at the phenotypic level and not yet at the genetic level. The present study investigates the genetic and environmental contributions to the association between borderline personality traits (BPT) and ADHD symptoms in a sample of 7,233 twins and siblings (aged 18–90 years) registered with the Netherlands Twin Register and the East Flanders Prospective Twin Survey (EFPTS) . Participants completed the Conners' Adult ADHD Rating Scales (CAARS‐S:SV) and the Personality Assessment Inventory‐Borderline Features Scale (PAI‐BOR). A bivariate genetic analysis was performed to determine the extent to which genetic and environmental factors influence variation in BPT and ADHD symptoms and the covariance between them. The heritability of BPT and ADHD symptoms was estimated at 45 and 36%, respectively. The remaining variance in BPT and ADHD symptoms was explained by unique environmental influences. The phenotypic correlation between BPT and ADHD symptoms was estimated at r = 0.59, and could be explained for 49% by genetic factors and 51% by environmental factors. The genetic and environmental correlations between BPT and ADHD symptoms were 0.72 and 0.51, respectively. The shared etiology between BPT and ADHD symptoms is thus a likely cause for the comorbidity of the two disorders. © 2011 Wiley‐Liss, Inc.     

Genetic and environmental influences on item response pattern scalability

Numerous studies have examined how genetic and environmental factors determine individual differences on multi-item personality scales. Few studies, however, have examined how genes and the environment influence the route by which individuals obtain their scores on these scales. Specifically, on a multi-item test, dozens of item response patterns result in equivalent total scores, though some response patterns are more likely to be observed than others. For many scales it may be of interest to determine the genetic and environmental influences on the item responsepatterns, as well as the sum of the item responses. We discuss a latent trait measure of item response pattern scalability, called Z_l (Levine and Drasgow, 1982), and investigate the properties of this index from a behavioral genetics perspective. Using a large sample of identical and fraternal twins from the Minnesota Twin Registry (Lykkenet al., 1990), item response pattern scalability is shown to be moderately heritable. On the four scales of the Multidimensional Personality Questionnaire (Tellegen, 1982) that were investigated, approximately 20% of the variation in scalability was due to genetic diversity between subjects of our sample. Follow-up analyses, using a factor-analytically based, genotype-environment model of item response behavior, indicated that specific genetic and environmental factors play a substantial role in determining item response pattern variation.This work was funded in part by Grant MH37860 from The National Institute of Mental Health.     

The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes

Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the 'missing heritability problem'. Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complimentary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility as well as novel candidate genes enriched for functions related to T cell receptor signaling and adenosine triphosphate synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility.