Over the past several years, evidence has accumulated showing that the cerebellum plays a significant role in cognitive function. Here we show, in a large genetically informative twin sample (n = 430; aged 16–30 years), that the cerebellum is strongly, and reliably (n = 30 rescans), activated during an n-back working memory task, particularly lobules I–IV, VIIa Crus I and II, IX and the vermis. Monozygotic twin correlations for cerebellar activation were generally much larger than dizygotic twin correlations, consistent with genetic influences. Structural equation models showed that up to 65% of the variance in cerebellar activation during working memory is genetic (averaging 34% across significant voxels), most prominently in the lobules VI, and VIIa Crus I, with the remaining variance explained by unique/unshared environmental factors. Heritability estimates for brain activation in the cerebellum agree with those found for working memory activation in the cerebral cortex, even though cerebellar cyto-architecture differs substantially. Phenotypic correlations between BOLD percent signal change in cerebrum and cerebellum were low, and bivariate modeling indicated that genetic influences on the cerebellum are at least partly specific to the cerebellum. Activation on the voxel-level correlated very weakly with cerebellar gray matter volume, suggesting specific genetic influences on the BOLD signal. Heritable signals identified here should facilitate discovery of genetic polymorphisms influencing cerebellar function through genome-wide association studies, to elucidate the genetic liability to brain disorders affecting the cerebellum.
Cerebellum; Heritability; Genetics; Functional MRI; Working memory; Twin study
People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the aetiology of these important psychiatric disorders.
To undertake a comprehensive genome-wide linkage study of neuroticism, using large study samples that have been measured multiple times. To compare the results between countries for replication and across time within countries for consistency.
Genome wide linkage scan.
Twin individuals and their family members from Australia (AU) and the Netherlands (NL).
19,635 sibling pairs completed self-report questionnaires for neuroticism up to five times over a period of up to 22 years. 5,069 sibling pairs were genotyped with microsatellite markers.
Non-parametric linkage analyses were conducted in Merlin-Regress for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time specific measures of neuroticism from each country to investigate consistency of linkage results.
Three chromosomal regions exceeded empirically-derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 cM (NL), 14q 103 cM (NL) and 18q 117 cM (AU & NL combined), but only 14q retains significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and one (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice.
Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbour causal variants for neuroticism and its related psychiatric disorders and can inform prioritisation of results from genome-wide association studies.
Understanding how the brain matures in healthy individuals is critical for evaluating deviations from normal development in psychiatric and neurodevelopmental disorders. The brain’s anatomical networks are profoundly re-modeled between childhood and adulthood, and diffusion tractography offers unprecedented power to reconstruct these networks and neural pathways in vivo. Here we tracked changes in structural connectivity and network efficiency in 439 right-handed individuals aged 12 to 30 (211 female/126 male adults, mean age=23.6, SD=2.19; 31 female/24 male 12 year olds, mean age=12.3, SD=0.18; and 25 female/22 male 16 year olds, mean age=16.2, SD=0.37). All participants were scanned with high angular resolution diffusion imaging (HARDI) at 4 Tesla. After we performed whole brain tractography, 70 cortical gyral-based regions of interest were extracted from each participant’s co-registered anatomical scans. The degree of fiber connections between all pairs of cortical regions, or nodes, were found to create symmetric fiber density matrices, reflecting the structural brain network. From those 70×70 matrices we computed graph theory metrics characterizing structural connectivity. Several key global and nodal metrics changed across development, showing increased network integration, with some connections pruned and others strengthened. The increases and decreases in fiber density, however, were not distributed proportionally across the brain. The frontal cortex had a disproportionate number of decreases in fiber density while the temporal cortex had a disproportionate number of increases in fiber density. This large-scale analysis of the developing structural connectome offers a foundation to develop statistical criteria for aberrant brain connectivity as the human brain matures.
HARDI; structural connectivity; graph theory; development
Visual impairment is a leading cause for morbidity and poor quality of life in our community. Unravelling the mechanisms underpinning important blinding diseases could allow for preventative or curative steps to be implemented. Twin siblings provide a unique opportunity in biology to discover genes associated with numerous eye diseases and ocular biometry. Twins are particularly useful for quantitative trait analysis through genome-wide association and linkage studies. Although many studies involving twins rely on twin registries, we present our approach to the Twins Eye Study in Tasmania to provide insight into possible recruitment strategies, expected participation rates and potential examination strategies that can be considered by other researchers for similar studies. Five separate avenues for cohort recruitment were adopted: 1) piggy-backing existing studies where twins had been recruited; 2); utilising the national twin registry; 3) word of mouth and local media publicity; 4) directly approaching schools; and finally 5) collaborating with other research groups studying twins.
Ophthalmology; glaucoma; myopia; genetics; genome-wide association
The direction of causation between measures of disrupted sleep, anxiety and depression is not well understood. Under certain conditions, cross sectional analysis based on genetically informative data can provide important information about the direction of causation between variables. Two community-based samples of 7,235 Australian twins aged 18 to 87 years were mailed an extensive questionnaire that covered a wide range of personality and behavioral measures. Included were self-report measures of disrupted sleep as well as symptoms of anxiety and depression. Among all females, modeling the direction of causation did not support the hypothesis of sleep having a direct causal impact on risk of anxiety or depression. Among older females, we found evidence that both anxiety and depression interact reciprocally with disrupted sleep whereas among younger women, both anxiety and depression appear to have a causal impact on sleep. Results for males were equivocal. The nosological implications of our findings are discussed.
Disrupted sleep; anxiety; depression; twins; genes; environment; direction of causation
Variation in alcohol metabolism affects the duration of intoxication
and alcohol use. While the majority of genetic association studies
investigating variation in alcohol metabolism have focused on polymorphisms
in alcohol or aldehyde dehydrogenases, we have now tested for association
with genes in alternative metabolic pathways that catalyze the carbon
skeleton of ethanol and NADH reoxidation.
950 single nucleotide polymorphisms (SNPs) spanning 14 genes
(ACN9, ACSS1, ACSS2,
ALDH1A1, CAT, CYP2E1, GOT1,
GOT2, MDH1, MDH2,
SLC25A12, SLC25A13) were genotyped in
352 young adults who participated in an alcohol challenge study. Traits
tested were blood and breath alcohol concentration, peak alcohol
concentration and rates of alcohol absorption and elimination. Allelic
association was tested using quantitative univariate and multivariate
A CYP2E1 promoter SNP (rs4838767, minor allele
frequency 0.008) exceeded the threshold for study-wide significance (4.01
× 10−5) for two early blood alcohol concentration
(BAC), eight breath alcohol concentration (BrAC) measures and the peak BrAC.
For each phenotype the minor C-allele was related to a lower alcohol
concentration, most strongly for the fourth BrAC (P = 2.07 ×
10−7) explaining ~8% of the phenotypic
variance. We also observed suggestive patterns of association with variants
in ALDH1A1 and on chromosome 17 near
SLC25A11 for aspects of blood and breath alcohol
metabolism. A SNP upstream of GOT1 (rs2490286) reached
study-wide significance for multivariate BAC metabolism (P =
Overall, we did not find strong evidence that variation in genes
coding for proteins that further metabolize the carbon backbone of
acetaldehyde, or contribute to mechanisms for regenerating NAD from NADH,
affects alcohol metabolism in our European-descent subjects. However, based
on the breath alcohol data, variation in the promoter of
CYP2E1 may play a role in pre-absorptive or early
hepatic alcohol metabolism, but more samples are required to validate this
alcohol metabolism; association; genetics; CYP2E1; alcohol challenge
Schizotypy is phenotypically associated with neuroticism. To reveal the origin of this association, we assessed 3349 (1449 monozygotic (MZ), 1105 dizygotic (DZ) same-sex and 795 DZ opposite-sex) twins on a 12-item version of Chapman’s Psychosis-Proneness Scales and the short-form of the Eysenck Personality Questionnaire-Revised as measures of schizotypy and neuroticism.
A substantial proportion (.51 with 95% CI from .38 to .64) of the phenotypic correlation of .37 between neuroticism and the perceptual and ideational components of schizotypy was accounted for by shared genetic influences on these two traits. Moreover, a Cholesky decomposition including anhedonia, hypomania and impulsivity fully accounted for the heritable variance in perceptual and ideational components of schizotypy.
These findings suggest a shared genetic etiology between neuroticism and perceptual and ideational components of schizotypy and affect future investigations on the etiology of these phenotypically overlapping traits and affective and psychotic disorders.
Perceptual aberration; Magical ideation; Phenotypic correlation; Behavior genetics; Schizotypy; Neuroticism
This study sought to determine the relationship between BMI fluctuation and cardiovascular disease phenotypes, diabetes, and depression and the role of genetic and environmental factors in individual differences in BMI fluctuation using the extended twin-family model (ETFM).
Study Design and Methods
This study included 14,763 twins and their relatives. Health and Lifestyle Questionnaires were obtained from 28,492 individuals from the Virginia 30,000 dataset including twins, parents, siblings, spouses, and children of twins. Self-report cardiovascular disease, diabetes, and depression data were available. From self-reported height and weight, BMI fluctuation was calculated as the difference between highest and lowest BMI after age 18, for individuals 18–80 years. Logistic regression analyses were used to determine the relationship between BMI fluctuation and disease status. The ETFM was used to estimate the significance and contribution of genetic and environmental factors, cultural transmission, and assortative mating components to BMI fluctuation, while controlling for age. We tested sex differences in additive and dominant genetic effects, parental, non-parental, twin, and unique environmental effects.
BMI fluctuation was highly associated with disease status, independent of BMI. Genetic effects accounted for ~34% of variance in BMI fluctuation in males and ~43% of variance in females. The majority of the variance was accounted for by environmental factors, about a third of which were shared among twins. Assortative mating, and cultural transmission accounted for only a small proportion of variance in this phenotype.
Since there are substantial health risks associated with BMI fluctuation and environmental components of BMI fluctuation account for over 60% of variance in males and over 50% of variance in females, environmental risk factors may be appropriate targets to reduce BMI fluctuation.
BMI; Chronic Disease; Weight change; Heritability; Family Studies
Cannabis is the most widely used illicit drug throughout the developed world and there is consistent evidence of heritable influences on multiple stages of cannabis involvement including initiation of use and abuse/dependence. In this paper, we describe the methodology and preliminary results of a large-scale interview study of 3,824 young adult twins (born 1972–1979) and their siblings. Cannabis use was common with 75.2% of males and 64.7% of females reporting some lifetime use of cannabis while 24.5% of males and 11.8% of females reported meeting criteria for DSM-IV cannabis abuse or dependence. Rates of other drug use disorders and common psychiatric conditions were highly correlated with extent of cannabis involvement and there was consistent evidence of heritable influences across a range of cannabis phenotypes including early (≤15 years) opportunity to use (h2 = 72%), early (≤16 years) onset use (h2 = 80%), using cannabis 11+ times lifetime (h2 = 76%), and DSM abuse/dependence (h2 = 72%). Early age of onset of cannabis use was strongly associated with increased rates of subsequent use of other illicit drugs and with illicit drug abuse/dependence; further analyses indicating that some component of this association may have been mediated by increasing exposure to and opportunity to use other illicit drugs.
Cannabis; twin; Comorbidity; Illicit drugs
The development of late-onset Alzheimer’s disease (LOAD) is under strong genetic control and there is great interest in the genetic variants that confer increased risk. The Alzheimer’s disease risk gene, growth factor receptor bound protein 2-associated protein (GAB2), has been shown to provide a 1.27–1.51 increased odds of developing LOAD for rs7101429 major allele carriers, in case-control analysis. GAB2 is expressed across the brain throughout life, and its role in LOAD pathology is well understood. Recent studies have begun to examine the effect of genetic variation in the GAB2 gene on differences in the brain. However, the effect of GAB2 on the young-adult brain has yet to be considered. Here we found a significant association between the GAB2 gene and morphological brain differences in 755 young-adult twins (469 females) (M = 23.1, SD = 3.1 years), using a gene-based test with principal components regression (PCReg). Detectable differences in brain morphology are therefore associated with variation in the GAB2 gene, even in young adults, long before the typical age of onset of Alzheimer’s disease.
GAB2; imaging genetics; tensor-based morphometry; Alzheimer’s disease
Several common genetic variants have recently been discovered that appear to influence white matter microstructure, as measured by diffusion tensor imaging (DTI). Each genetic variant explains only a small proportion of the variance in brain microstructure, so we set out to explore their combined effect on the white matter integrity of the corpus callosum. We measured six common candidate single-nucleotide polymorphisms (SNPs) in the COMT, NTRK1, BDNF, ErbB4, CLU, and HFE genes, and investigated their individual and aggregate effects on white matter structure in 395 healthy adult twins and siblings (age: 20–30 years). All subjects were scanned with 4-tesla 94-direction high angular resolution diffusion imaging. When combined using mixed-effects linear regression, a joint model based on five of the candidate SNPs (COMT, NTRK1, ErbB4, CLU, and HFE) explained ∼6% of the variance in the average fractional anisotropy (FA) of the corpus callosum. This predictive model had detectable effects on FA at 82% of the corpus callosum voxels, including the genu, body, and splenium. Predicting the brain's fiber microstructure from genotypes may ultimately help in early risk assessment, and eventually, in personalized treatment for neuropsychiatric disorders in which brain integrity and connectivity are affected.
neuroimaging; brain structure; DTI; genetics; genetic profiles; prediction; imaging; clinical or preclinical; neuroanatomy; neurogenetics; pharmacogenetics / pharmacogenomics; neuroimaging; brain structure; DTI; genetics; genetic profiles
The patient population of borderline personality disorder (BPD) is heterogeneous; many different combinations of BPD symptoms can lead to a BPD diagnosis. We investigated to what extent the covariance among four main components of BPD is explained by shared genetic and environmental factors. Using an extended twin design, multivariate genetic models were applied to the scales of the PAI-BOR, a self-report questionnaire tapping four main features of BPD (affective instability, identity problems, negative relationships, and self-harm). Data on the four BPD scales were available for 5,533 twins and 1,202 siblings from the Netherlands, Belgium, and Australia. The correlations among the scales ranged from 0.23 to 0.50 and were best explained by a genetic common pathway model. This model specifies that genes and environment influence the covariance between four main features of BPD in qualitatively similar ways, through a single latent factor representing the BPD construct. The heritability of the latent BPD factor was 51% and the remainder of its variance was explained by unique environmental influences. For each BPD scale, except self-harm, around 50% of its variance was explained by the latent BPD factor. The remaining variance for each of the four scales was explained by genetic (4% for affective instability to 20% for self-harm) and environmental (38% for negative relationships to 67% for self-harm) factors that were specific to each scale.
The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited.
To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and further, to replicate this interaction in an independent sample.
Genetic association study in 1041 young adult U.S. women with replication in an independent Australian sample of 1428 heroin dependent cases and 506 neighborhood controls.
Main outcome measure
Self-reported anhedonia and depression (with anhedonia).
In both samples, those who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with one or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in those reporting childhood physical abuse, while 57% of those homozygous for the major allele reported anhedonia, only 29% of those who were carriers of the minor allele reported it (p < 0.02). rs1049353 also buffered the effects of childhood physical abuse on major depressive disorder, however this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, where minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse.
Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer and hence, future studies should carefully examine its impact on expression and conformational variation in CNR1, particularly in relation to stress adaptation.
CNR1; endocannabinoid; physical abuse; rs1049353; GxE; anhedonia; major depression
This study demonstrates a novel approach to test associations between highly heterogeneous genetic loci and complex phenotypes. Previous investigations of the relationship between Cytochrome P450 2A6 (CYP2A6) genotype and smoking phenotypes made comparisons by dividing subjects into broad categories based on assumptions that simplify the range of function of different CYP2A6 alleles, their numerous possible diplotype combinations and non-additive allele effects. A predictive model that translates CYP2A6 diplotype into a single continuous variable was previously derived from an in vivo metabolism experiment in 189 European Americans. Here, we apply this model to assess associations between genotype, inferred nicotine metabolism and smoking behaviors in larger samples without direct nicotine metabolism measurements. CYP2A6 genotype is not associated with nicotine dependence, as defined by the Fagerström Test of Nicotine Dependence, demonstrating that cigarettes smoked per day (CPD) and nicotine dependence have distinct genetic correlates. The predicted metric is significantly associated with CPD among African Americans and European American dependent smokers. Individual slow metabolizing genotypes are associated with lower CPD, but the predicted metric is the best predictor of CPD. Furthermore, optimizing the predictive model by including additional CYP2A6 alleles improves the fit of the model in an independent data set and provides a novel method of predicting the functional impact of alleles without direct metabolism measurements. Lastly, comprehensive genotyping and in vivo metabolism data are used to demonstrate that genome-wide significant associations between CPD and single nucleotide polymorphisms are the result of synthetic associations.
Twin pairs and their siblings rated the intensity of the odorants amyl acetate,
androstenone, eugenol, Galaxolide, mercaptans, and rose (N =
1573). Heritability was established for ratings of androstenone (h
2 = 0.30) and Galaxolide (h2 = 0.34) but not for the other odorants. Genome-wide association analysis
using 2.3 million single nucleotide polymorphisms indicated that the most significant
association was between androstenone and a region without known olfactory receptor genes
(rs10966900, P = 1.2 ×
10−7). A previously reported association between the olfactory receptor
OR7D4 and the androstenone was not detected until we specifically typed
this gene (P = 1.1 × 10−4). We also tested
these 2 associations in a second independent sample of subjects and replicated the results
either fully (OR7D4, P = 0.00002) or partially
(rs10966900, P = 0.010; N
= 266). These findings suggest that 1) the perceived intensity of some but not all
odorants is a heritable trait, 2) use of a current genome-wide marker panel did not detect
a known olfactory genotype–phenotype association, and 3) person-to-person
differences in androstenone perception are influenced by OR7D4 genotype
and perhaps by variants of other genes.
androstenone; Galaxolide; genetic twin modeling; genome-wide association study; heritability; twins
The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examine the role of three intensively studied single nucleotide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use. Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examination) Survey. The combined sample included a total of 32,592 adult Finns (54% women) of whom 8,356 were assessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals. We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample. As a conclusion, our results provide further evidence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765 (locus 3) may be specific to alcohol use as the effect is seen also in never smokers.
Nicotinic acetylcholine receptors; 15q25.1; alcohol use; smoking behavior; public health; population-based sample; genetic association
Cutaneous malignant melanoma (CMM) is a major health issue in Queensland, Australia which has the world’s highest incidence. Recent molecular and epidemiologic studies suggest that CMM arises through multiple etiological pathways involving gene-environment interactions. Understanding the potential mechanisms leading to CMM requires larger studies than those previously conducted. This article describes the design and baseline characteristics of Q-MEGA, the Queensland study of Melanoma: Environmental and Genetic Associations, which followed-up four population-based samples of CMM patients in Queensland, including children, adolescents, men aged over 50, and a large sample of adult cases and their families, including twins. Q-MEGA aims to investigate the roles of genetic and environmental factors, and their interaction, in the etiology of melanoma. 3,471 participants took part in the follow-up study and were administered a computer-assisted telephone interview in 2002–2005. Updated data on environmental and phenotypic risk factors, and 2,777 blood samples were collected from interviewed participants as well as a subset of relatives. This study provides a large and well-described population-based sample of CMM cases with follow-up data. Characteristics of the cases and repeatability of sun exposure and phenotype measures between the baseline and the follow-up surveys, from six to 17 years later, are also described.
We have previously described the role of red hair (Melanocortin 1 Receptor, MC1R) and blue eye (Oculocutaneous Albinism Type 2, OCA2) gene polymorphisms in modulating risk of cutaneous malignant melanoma (CMM) in a highly sun-exposed population of European descent. A number of recent studies, including genome-wide association studies (GWAS), have identified numerous polymorphisms controlling human hair, eye and skin colour. In this paper, we test a selected set of polymorphisms in pigmentation loci (ASIP, TYR, TYRP1, MC1R, OCA2, IRF4, SLC24A4, SLC45A2) for association with CMM risk in a large Australian population-based case control study. Variants in IRF4 and SLC24A4, despite being strongly associated with pigmentation in our sample, did not modify CMM risk, but the other six did. Three SNPs (rs28777, rs35391, rs16891982) in the MATP gene (SLC45A2) exhibited the strongest crude association with risk, but this was attenuated to approximately the same effect size as that of a MC1R red hair color allele by controlling for ancestry of cases and controls. We also detected significant epistatic interactions between SLC45A2 and OCA2 alleles, and MC1R and ASIP alleles. Overall, these measured variants account for 12% of the familial risk of CMM in our population.
The prevalence of cutaneous malignant melanoma (CMM) has increased significantly in most Caucasian populations in recent decades. Both genetic and environment are significant risk factors involved in the development of CMM. A germline mutation in the Syntaxin 17 (STX17) gene was recently identified in horses causing premature hair gray and associated with susceptibility to melanoma. We hypothesized that common germline variants in the STX17 gene might be associated with predisposition to human CMM or might interact with other melanoma risk genes. We conducted a case-control study by genotyping 26 tagging single nucleotide polymorphisms (SNPs) across the STX17 gene region in an Australian sample and performed logistic regression analysis for predicting the possible SNP interactions in a combined dataset. Our results do not support an association between CMM and any of the STX17 SNPs and provide no evidence for interactions between the melanoma risk SNP rs910873 on chromosome 20 and any of the STX17 SNPs. We conclude that common variants in the STX17 gene region do not play a key role in the pathogenesis of human melanoma.
Syntaxin 17; melanoma; polymorphisms
The cardiometabolic syndrome comprised of multiple correlated traits, but its origin is incompletely understood. Chromogranin A (CHGA) is required for formation of the catecholamine secretory pathway in sympathochromaffin cells. In twin pair studies, we found that CHGA traits aggregated with body mass index (BMI), as well as its biochemical determinant leptin.
Here we used the twin method to probe the role of heredity in generating such risk traits, and then investigated the role of risk-trait-associated CHGA promoter genetic variation in transfected chromaffin cells. Trait heritability (h2) and shared genetic determination among traits (pleiotropy, genetic covariance, ρG) were estimated by variance components in twin pairs.
CHGA, BMI, and leptin each displayed substantial h2, and the traits also aggregated with several features of the metabolic syndrome (e.g., insulin resistance, blood pressure (BP), hypertension, catecholamines, and C-reactive protein (CRP)). Twin studies demonstrated genetic covariance (pleiotropy, ρG) for CHGA, BMI, and leptin with other metabolic traits (insulin resistance, BP, and CRP). We therefore investigated the CHGA locus for mechanisms of codetermination with such metabolic traits. A common functional variant in the human CHGA promoter (G-462A, rs9658634, minor allele frequency ~21%) was associated with leptin and CRP secretion, as well as BMI, especially in women; marker-on-trait effects on BMI were replicated across twin populations on two continents. In CHGA promoter/luciferase reporter plasmids transfected into chromaffin cells, G-462A alleles differed markedly in reporter expression. The G-462A variant disrupted predicted transcriptional control by a PPARγ/RXRα motif and costimulation by PPARγ/RXRα and their cognate ligands, differentially activated the two alleles. During chromatin immunoprecipitation, endogenous PPARγ bound the motif.
Multiple features of the metabolic syndrome are thus under joint (pleiotropic) genetic determination, with CHGA as one such contributory locus: a common polymorphism in the promoter (G-462A) of CHGA predicts such heritable metabolic traits as BMI and leptin. CHGA promoter variant G-462A was not only associated with such metabolic traits but also disrupted a PPARγ/RXRα motif and responded differentially to characteristic trans-activators of that motif. The results suggest novel links between the catecholaminergic system and risk for the metabolic syndrome as well as systemic hypertension.
adrenal; blood pressure; BMI; C-reactive protein; catecholamine; chromaffin; chromogranin; hypertension; leptin; metabolic syndrome; twin study
While there is solid evidence that cannabis use is heritable, attempts to identify genetic influences at the molecular level have yielded mixed results. Here, a large twin family sample (N=7452) was used to test for association between ten previously reported candidate genes and lifetime frequency of cannabis use using a gene-based association test. None of the candidate genes reached even nominal significance (p<.05). The lack of replication may point to our limited understanding of the neurobiology of cannabis involvement and also to potential publication bias and false-positive findings in previous studies.
genes; cannabis; genetics; association
Traits that are attractive to the opposite sex are often positively correlated when scaled such that scores increase with attractiveness, and this correlation typically has a genetic component. Such traits can be genetically correlated due to genes that affect both traits (“pleiotropy”) and/or because assortative mating causes statistical correlations to develop between selected alleles across the traits (“gametic phase disequilibrium”). In this study, we modeled the covariation between monozygotic and dizygotic twins, their siblings, and their parents (total N = 7,905) to elucidate the nature of the correlation between two potentially sexually selected traits in humans: height and IQ. Unlike previous designs used to investigate the nature of the height–IQ correlation, the present design accounts for the effects of assortative mating and provides much less biased estimates of additive genetic, non-additive genetic, and shared environmental influences. Both traits were highly heritable, although there was greater evidence for non-additive genetic effects in males. After accounting for assortative mating, the correlation between height and IQ was found to be almost entirely genetic in nature. Model fits indicate that both pleiotropy and assortative mating contribute significantly and about equally to this genetic correlation.
Traits that are attractive to the opposite sex are often positively correlated when scaled such that scores increase with attractiveness, and this correlation typically has a genetic component. Such traits can be genetically correlated due to genes that affect both traits and/or because assortative mating (people choosing mates who are similar to themselves) causes statistical correlations to develop between selected alleles across the traits. In this study, we used a large (total N = 7,905), genetically informative dataset to understand why two potentially sexually selected traits in humans—height and IQ—are correlated. We found that both shared genes and assortative mating were about equally important in causing the relationship between these two traits. To our knowledge, this is the first study that has been able to disambiguate the two principal reasons—shared genes versus assortative mating—for why traits can be genetically correlated.
Irregularity in the corneal curvature (CC) is highly associated with various eye disorders such as keratoconus and myopia. The sample had limited power to find genomewide significant (5 × 10−8) hits but good power for replication. Thus, an attempt was made to test whether alleles in the FRAP1 and PDGFRA genes, recently found to be associated with CC in Asian populations, also influence CC in Australians of North European ancestry. Results of initial genomewide association studies (GWAS) for CC in Australians were also reported.
Two population-based cohorts of 1788 Australian twins and their families, as well as 1013 individuals from a birth cohort from Western Australia, were genotyped using genomewide arrays. Following separate individual analysis and quality control, the results from each cohort underwent meta-analysis.
Meta-analysis revealed significant replication of association between rs2114039 and corneal curvature (P = 0.0045). The SNP rs2114039 near PDGFRA has been previously implicated in Asians. No SNP at the FRAP1 locus was found to be associated in our Australian samples. No SNP surpassed the genomewide significance threshold of 5 × 10−8. The SNP with strongest association was rs2444240 (P = 3.658 × 10−7), which is 31 kb upstream to the TRIM29 gene.
A significant role of the PDGFRA gene in determining corneal curvature in the Australian population was confirmed in this study, also highlighting the putative association of the TRIM29 locus with CC.
Corneal curvature (CC) is a risk factor for various vision disorders including keratoconus and myopia. This study reports association of the PDGFRA gene with CC in the Australian population, which was previously found to be associated in an Asian population. It also reports initial GWAS findings on CC in Australians.
We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.