IQ predicts many measures of life success, as well as trajectories of brain development. Prolonged cortical thickening observed in individuals with higher IQ might reflect an extended period of synaptogenesis and high environmental sensitivity or plasticity. We tested this hypothesis by examining the timing of changes in the magnitude of genetic and environmental influences on IQ as a function of IQ score. We find that individuals with higher IQ show high environmental influence on IQ into adolescence (resembling younger children), whereas individuals with lower IQ show high heritability of IQ in adolescence (resembling adults), consistent with an extended sensitive period for intellectual development in more intelligent individuals. These patterns hold across a cross-sectional sample of almost 11,000 twin pairs, and a longitudinal sample of twins, biological siblings, and adoptive siblings.
Intelligence; Behavior Genetics; Individual Differences; Cognitive Development; Cognitive Ability
Automatic labeling of white matter fibres in diffusion-weighted brain MRI is vital for comparing brain integrity and connectivity across populations, but is challenging. Whole brain tractography generates a vast set of fibres throughout the brain, but it is hard to cluster them into anatomically meaningful tracts, due to wide individual variations in the trajectory and shape of white matter pathways. We propose a novel automatic tract labeling algorithm that fuses information from tractography and multiple hand-labeled fibre tract atlases. As streamline tractography can generate a large number of false positive fibres, we developed a top-down approach to extract tracts consistent with known anatomy, based on a distance metric to multiple hand-labeled atlases. Clustering results from different atlases were fused, using a multi-stage fusion scheme. Our “label fusion” method reliably extracted the major tracts from 105-gradient HARDI scans of 100 young normal adults.
Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9–85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large “mega-family”. We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability.
Diffusion Tensor Imaging (DTI); Imaging Genetics; Heritability; Meta-analysis; Multi-site; Reliability
Posttraumatic stress disorder (PTSD), a pathologic response to severe
stress, is a common comorbid disorder in substance dependent individuals.
Evidence from twin studies suggests PTSD is moderately heritable. Genetic
association studies to date have reported a limited number of replicated
findings. We conducted a candidate gene association study in trauma-exposed
individuals within the Comorbidity and Trauma Study’s sample (1343
heroin dependent cases and 406 controls from economically-disadvantaged
neighborhoods). After data cleaning, the 1430 SNPs retained for analyses
provided coverage of 72 candidate genes and included additional SNPs for which
association was previously reported as well as 30 ancestry informative markers.
We found a functional DRD2 promoter polymorphism (rs12364283)
to be most highly associated with PTSD liability [OR 1.65
(1.27–2.15); p= 1.58 × 10−4];
however, this association was not significant with a stringent Bonferroni
correction for multiple comparisons. The top hits include SNPs from other
dopaminergic system genes: DRD2 DRD3, TH, and
DBH. Additional analyses revealed the association involving
rs12364283 is largely limited to amphetamine dependent individuals. Substantial
risk is observed in amphetamine dependent individuals with at least one copy of
this SNP [OR 2.86 (1.92–4.27); p=2.6 ×
10−7]. Further analyses do not support extensive
mediation of PTSD risk via self-reported impulsivity (BIS total score). These
findings suggest roles for impairment in inhibitory control in the
pathophysiology of PTSD and raise questions about stimulant use in certain
populations (e.g., those in combat).
amphetamine dependence; association study; DRD2; PTSD
We have compared the melanogenic activities of cultured melanocytes carrying two common TYR alleles as homozygous 192S-402R wildtype, heterozygous and homozygous variant. This includes assays of TYR protein, DOPAoxidase activity, glycosylation and temperature sensitivity of protein and DOPAoxidase levels. Homozygous wildtype strains on average had higher levels of TYR protein and enzyme activity than other genotypes. Homozygous 402Q/Q melanocytes produced significantly less TYR protein, displayed altered trafficking and glycosylation, with reduced DOPAoxidase. However, near wildtype TYR activity levels could be recovered at lower growth temperature. In a sample population from Southeast Queensland these two polymorphisms were present on four TYR haplotypes, designated as WT 192S-402R, 192Y-402R, 192S-402Q with a double variant 192Y-402Q of low frequency at 1.9%. Based on cell culture findings and haplotype associations, we have used an additive model to assess the penetrance of the ten possible TYR genotypes derived from the combination of these haplotypes.
Tyrosinase; Pigmentation; Melanocyte; Albinism; Melanin
Recently, carriers of a common variant in the autism risk gene, CNTNAP2, were found to have altered functional brain connectivity using functional MRI. Here we scanned 328 young adults with high-field (4-Tesla) diffusion imaging, to test the hypothesis that carriers of this gene variant would have altered structural brain connectivity. All participants (209 females, 119 males, age: 23.4 +/−2.17 SD years) were scanned with 105-gradient high angular diffusion imaging (HARDI) at 4 Tesla. After performing a whole-brain fiber tractography using the full angular resolution of the diffusion scans, 70 cortical surface-based regions of interest were created from each individual’s co-registered anatomical data to compute graph metrics for all pairs of cortical regions. In graph theory analyses, subjects homozygous for the risk allele (CC) had lower characteristic path length, greater small-worldness and global efficiency in whole brain analyses, as well as greater eccentricity (maximum path length) in 60 of 70 nodes in regional analyses. These results were not reducible to differences in more commonly studied traits such as fiber density or fractional anisotropy. This is the first study to link graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of circuits implicated in risk for autism.
structural connectivity; HARDI; autism; CNTNAP2; graph theory; twins
To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis.
Cases = 3,223 women with surgically confirmed endometriosis; Controls = 1,190 women without endometriosis and 7,060 population samples.
Analysis of 11,984 SNPs on chromosome 10.
Main outcome measure(s)
Allele frequency differences between cases and controls.
Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds (LOD) score = 3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737, P=4.9 × 10−4), 105.63 Mb (rs1253130, P=2.5 × 10−4) and 124.25 Mb (rs2250804, P=9.7 × 10−4). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7060 population controls.
The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.
Endometriosis; linkage; association; subfertility; CYP2C19
Non-suicidal and suicidal self-injury are very harmful behaviours and are associated with several psychiatric disorders. In the recently developed 5th version of the DSM, non-suicidal self-injury and suicidal behaviour disorder are for the first time introduced as conditions in their own right, instead of symptoms of other psychiatric disorders. It is unclear to what extent non-suicidal and suicidal self-injurious behaviours share the same underlying biological mechanisms and are influenced by the same environmental factors.
To determine the relative importance of genetic and environmental influences on the variation in non-suicidal self-injury and suicidal ideation and their covariation.
Classical twin design, using population-based twin sample in which twins participated in semi-structured telephone interviews between 1996 and 2009 which primarily focused on psychiatric disorders.
10678 male and female Australian adult twins (mean age 32.8 years).
Main Outcome Measures
Lifetime presence of self-reported non-suicidal self-injury (NSSI) and suicidal ideation.
The prevalence of NSSI and suicidal ideation was 4.7% and 26.5% and individuals that engaged in self-harm were much more likely to report suicidal ideation, OR(95%CIs)=8.4 (6.8–10.3). Results from a bivariate genetic model indicated that genetic factors explain a substantial part of the variance in both NSSI (37% for males and 59% for females) and suicidal ideation (41% and 55%, respectively), while residual influences (including nonshared environmental influences and measurement error) explain the remainder of the variance. Shared (family) environment did not seem to play a role. Moreover, both behaviours were strongly correlated (r=0.49 for males and 0.61 for females) and this correlation was largely explained by overlapping genetic influences (62% and 76% for males and females, respectively), whereas residual influences accounted for the remainder of the phenotypic correlation.
Conclusions and Relevance
Results indicated that the substantial correlation between NSSI and suicidal ideation is largely driven by overlapping genetic factors, suggesting that the two behaviours share similar biological underpinnings. Overlapping residual influences also explain part of the covariance between the two traits. Future research should further investigate which genetic and environmental influences underlie the vulnerability in NSSI and suicidal ideation.
To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.
We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.
We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091).
At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6).
By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.
Rhinitis; atopy; selection; genetic correlation; bivariate; single nucleotide polymorphism
The purpose of this study was to determine whether Cloninger’s revised 7-factor model of personality showed incremental validity over his four dimensions of temperament. A sample of 2517 Australian twins aged over 50 between 1993 and 1995 returned completed self-reported measures of Self-directedness, Cooperativeness, and Self-transcendence from Cloninger’s Temperament and Character Inventory. Many of these twins had participated in a 1988 study containing Cloninger’s temperament measures of Harm Avoidance, Novelty Seeking, Reward Dependence and Persistence. Contrary to theoretical expectations, univariate analyses revealed that familial aggregation for the character dimensions could be entirely explained by additive gene action alone. Although temperament explained 26, 37 and 10% of additive genetic variance in Self-directedness, Cooperativeness and Self-transcendence, respectively, seven genetic factors were required to explain the genetic variance among the TPQ dimensions, and almost all of the non-shared environmental variance was unique to each dimension of character. Our results indicate that the inclusion of all seven dimensions in a taxonomy of personality is warranted.
Personality; Cloninger; Temperament; Character; Genes; Twins
In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-015-1559-0) contains supplementary material, which is available to authorized users.
In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10−
8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10−
4] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10−
9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46–4.70, P = 4.8 × 10−
69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
Almost forty years ago, evidence from large studies of adult twins and their relatives suggested that between 30-60% of the variance in social and political attitudes could be explained by genetic influences. However, these findings have not been widely accepted or incorporated into the dominant paradigms that explain the etiology of political ideology. This has been attributed in part to measurement and sample limitations, as well the relative absence of molecular genetic studies. Here we present results from original analyses of a combined sample of over 12,000 twins pairs, ascertained from nine different studies conducted in five democracies, sampled over the course of four decades. We provide evidence that genetic factors play a role in the formation of political ideology, regardless of how ideology is measured, the era, or the population sampled. The only exception is a question that explicitly uses the phrase “Left-Right”. We then present results from one of the first genome-wide association studies on political ideology using data from three samples: a 1990 Australian sample involving 6,894 individuals from 3,516 families; a 2008 Australian sample of 1,160 related individuals from 635 families and a 2010 Swedish sample involving 3,334 individuals from 2,607 families. No polymorphisms reached genome-wide significance in the meta-analysis. The combined evidence suggests that political ideology constitutes a fundamental aspect of one’s genetically informed psychological disposition, but as Fisher proposed long ago, genetic influences on complex traits will be composed of thousands of markers of very small effects and it will require extremely large samples to have enough power in order to identify specific polymorphisms related to complex social traits.
Ideology; Politics; GWAS; Attitudes; Authoritarianism
Human facial attractiveness and facial sexual dimorphism (masculinity–femininity) are important facets of mate choice and are hypothesized to honestly advertise genetic quality. However, it is unclear whether genes influencing facial attractiveness and masculinity–femininity have similar, opposing, or independent effects across sex, and the heritability of these phenotypes is poorly characterized. To investigate these issues, we assessed facial attractiveness and facial masculinity–femininity in the largest genetically informative sample (n = 1,580 same- and opposite-sex twin pairs and siblings) to assess these questions to date. The heritability was ~0.50–0.70 for attractiveness and ~0.40–0.50 for facial masculinity– femininity, indicating that, despite ostensible selection on genes influencing these traits, substantial genetic variation persists in both. Importantly, we found evidence for intralocus sexual conflict, whereby alleles that increase masculinity in males have the same effect in females. Additionally, genetic influences on attractiveness were shared across the sexes, suggesting that attractive fathers tend to have attractive daughters and attractive mothers tend to have attractive sons.
Facial attractiveness; Masculinity–femininity; Mate choice; Sexual selection; Intralocus sexual conflict; Evolutionary genetics; Twin and family studies; Sex limitation
Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here we analyse genetic association data on biochemical markers of iron status from eleven European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find eleven genome-wide-significant (p < 5 × 10−8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.
Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian clock genes and psychiatric disorders.
Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and Major Depressive Disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular clock influence risk to psychiatric disorders. Initially, gene-based and SNP p-values were analysed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analysed.
After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harboured no SNPs significant at the nominal level of p < 0.05, and none of the the variants identified in candidate studies of clock genes that were included in the PGC datasets were significant after correction for multiple testing. There was no evidence of an enrichment of associations in genes linked to control of circadian rhythms in human cells.
Our results suggest that genes encoding components of the molecular clock are not good candidates for harbouring common variants that increase risk to bipolar disorder, schizophrenia or Major Depressive Disorder.
Relational complexity (RC) is a metric reflecting capacity limitation in relational processing. It plays a crucial role in higher cognitive processes and is an endophenotype for several disorders. However, the genetic underpinnings of complex relational processing have not been investigated. Using the classical twin model, we estimated the heritability of RC and genetic overlap with intelligence (IQ), reasoning, and working memory in a twin and sibling sample aged 15-29 years (N = 787). Further, in an exploratory search for genetic loci contributing to RC, we examined associated genetic markers and genes in our Discovery sample and selected loci for replication in four independent samples (ALSPAC, LBC1936, NTR, NCNG), followed by meta-analysis (N>6500) at the single marker level. Twin modelling showed RC is highly heritable (67%), has considerable genetic overlap with IQ (59%), and is a major component of genetic covariation between reasoning and working memory (72%). At the molecular level, we found preliminary support for four single-marker loci (one in the gene DGKB), and at a gene-based level for the NPS gene, having influence on cognition. These results indicate that genetic sources influencing relational processing are a key component of the genetic architecture of broader cognitive abilities. Further, they suggest a genetic cascade, whereby genetic factors influencing capacity limitation in relational processing have a flow-on effect to more complex cognitive traits, including reasoning and working memory, and ultimately, IQ.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
Cannabis is the most commonly used illicit drug worldwide. With debate surrounding the legalization and control of use, investigating its health risks has become a pressing area of research. One established association is that between cannabis use and schizophrenia, a debilitating psychiatric disorder affecting approximately 1% of the population over their lifetime. Although considerable evidence implicates cannabis use as a component cause of schizophrenia, it remains unclear whether this is entirely due to cannabis directly raising risk of psychosis, or whether the same genes that increases psychosis risk may also increase risk of cannabis use.
In a sample of 2,082 healthy individuals, we show an association between an individual’s burden of schizophrenia risk alleles and use of cannabis. This was significant both for comparing those who have ever vs. never used cannabis (p=2.6×10−4), and for quantity of use within users (p=3.0×10−3). While directly predicting only a small amount of the variance in cannabis use, these findings suggest that part of the association between schizophrenia and cannabis is due to a shared genetic aetiology. This form of gene-environment correlation is an important consideration when calculating the impact of environmental risk factors, including cannabis use.
Two questions regarding sex differences in magical ideation were investigated in this study: (1) whether there are mean level sex differences on the Magical Ideation Scale (MIS), and (2) whether there are quantitative and/or qualitative sex differences in the genetic contributions to variation on this scale. These questions were evaluated using data obtained from a large community sample of adult Australian twins (N=4,355) that included opposite-sex pairs. Participants completed a modified 15-item version of the MIS within a larger assessment battery. Women reported both higher means and variability on the MIS than men; this was also observed within families (in opposite-sex twin pairs). Biometric modeling indicated that the proportion of variation in MIS scores due to genetic influences (indicating quantitative sex differences) and the specific latent genetic contributions to this variation (indicating qualitative sex differences) were the same in men and women. These findings clarify the nature of sex differences in magical ideation and point to avenues for future research.
magical ideation; sex differences; twin study; schizotypy; schizotypal personality disorder
Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma and IOP variability may herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multiethnic participants for IOP. We confirm genetic association of known loci for IOP and primary open angle glaucoma (POAG) and identify four new IOP loci located on chromosome 3q25.31 within the FNDC3B gene (p=4.19×10−08 for rs6445055), two on chromosome 9 (p=2.80×10−11 for rs2472493 near ABCA1 and p=6.39×10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best p=1.04×10−11 for rs747782). Separate meta-analyses of four independent POAG cohorts, totaling 4,284 cases and 95,560 controls, show that three of these IOP loci are also associated with POAG.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 advanced POAG cases and 1,992 controls. Association of the top SNPs from the discovery stage was investigated in two Australian replication cohorts (total 932 cases, 6,862 controls) and two US replication cohorts (total 2,616 cases, 2,634 controls). Meta-analysis of all cohorts revealed three novel loci associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493 [G] OR=1.31, P= 2.1 × 10-19), within AFAP1 (rs4619890 [G] OR=1.20, P= 7.0 × 10-10) and within GMDS (rs11969985 [G] OR=1.31, and P= 7.7 × 10-10). Using RT-PCR and immunolabelling, we also showed that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 advanced POAG cases and 1,992 controls. Association of the top SNPs from the discovery stage was investigated in two Australian replication cohorts (total 932 cases, 6,862 controls) and two US replication cohorts (total 2,616 cases, 2,634 controls). Meta-analysis of all cohorts revealed three novel loci associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493 [G] OR=1.31, P= 2.1 × 10−19), within AFAP1 (rs4619890 [G] OR=1.20, P= 7.0 × 10−10) and within GMDS (rs11969985 [G] OR=1.31, and P= 7.7 × 10−10). Using RT-PCR and immunolabelling, we also showed that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).
Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10−10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10−3 and 2×10−3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10−169 to 3.42×10−24.
We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.
Complex traits; Telomere; cancer: skin; melanoma