Narelle K. Hansell

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimers disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).

Meta-analysis of genome-wide association studies for personality

Personality can be thought of as a set of characteristics that influence peoples thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in 10 discovery samples (17 375 adults) and five in silico replication samples (3294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data of ∼2.4M single-nucleotide polymorphisms (SNPs; directly typed and imputed using HapMap data) were available. In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P=2.8 × 10−8 and 3.1 × 10−8) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P=4.9 × 10−8). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.

Common Variants in the Trichohyalin Gene Are Associated with Straight Hair in Europeans

Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining approximately 6% of variance (p=1.5x10(-31)). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations.

Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis

Alcohol dependence (AD) is a complex disorder with environmental and genetic origins. The role of two genetic variants in ALDH2 and ADH1B in AD risk has been extensively investigated. This study tested for associations between nine polymorphisms in ALDH2 and 41 in the seven ADH genes, and alcohol-related flushing, alcohol use and dependence symptom scores in 4597 Australian twins. The vast majority (4296) had consumed alcohol in the previous year, with 547 meeting DSM-IIIR criteria for AD. There were study-wide significant associations (P<2.3 x 10(-4)) between ADH1B-Arg48His (rs1229984) and flushing and consumption, but only nominally significant associations (P<0.01) with dependence. Individuals carrying the rs1229984 G-allele (48Arg) reported a lower prevalence of flushing after alcohol (P=8.2 x 10(-7)), consumed alcohol on more occasions (P=2.7 x 10(-6)), had a higher maximum number of alcoholic drinks in a single day (P=2.7 x 10(-6)) and a higher overall alcohol consumption (P=8.9 x 10(-8)) in the previous year than those with the less common A-allele (48His). After controlling for rs1229984, an independent association was observed between rs1042026 (ADH1B) and alcohol intake (P=4.7 x 10(-5)) and suggestive associations (P<0.001) between alcohol consumption phenotypes and rs1693482 (ADH1C), rs1230165 (ADH5) and rs3762894 (ADH4). ALDH2 variation was not associated with flushing or alcohol consumption, but was weakly associated with AD measures. These results bridge the gap between DNA sequence variation and alcohol-related behavior, confirming that the ADH1B-Arg48His polymorphism affects both alcohol-related flushing in Europeans and alcohol intake. The absence of study-wide significant effects on AD results from the low P-value required when testing multiple single nucleotide polymorphisms and phenotypes.

Childhood intelligence is heritable, highly polygenic and associated with FNBP1L.

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6–18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22–46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10−15, 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10−5), 3.5% (P=10−3) and 0.5% (P=6 × 10−5) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

Significance We identify several common genetic variants associated with cognitive performance using a two-stage approach: we conduct a genome-wide association study of educational attainment to generate a set of candidates, and then we estimate the association of these variants with cognitive performance. In older Americans, we find that these variants are jointly associated with cognitive health. Bioinformatics analyses implicate a set of genes that is associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. In addition to the substantive contribution, this work also serves to show a proxy-phenotype approach to discovering common genetic variants that is likely to be useful for many phenotypes of interest to social scientists (such as personality traits). We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness.

Central corneal thickness (CCT), one of the most highly heritable human traits (h2 typically>0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6×10−10. The locus on chromosome 16 was associated with CCT with p = 8.95×10−11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.

A genomewide association study of nicotine and alcohol dependence in Australian and Dutch populations

Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10,000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10(-8)) for ND (rs964170 in ARHGAP10 on chromosome 4, p = 4.43 x 10(-8)) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 (p = 1.90 x 10(-9)), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10(-9)) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10(-8))). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepresentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be required before the detailed causes of comorbidity between AD and ND are understood.

Alcohol Consumption Indices of Genetic Risk for Alcohol Dependence

BACKGROUND Previous research has reported a significant genetic correlation between heaviness of alcohol consumption and alcohol dependence (AD), but this association might be driven by the influence of AD on consumption rather than the reverse. We test the genetic overlap between AD symptoms and a heaviness of consumption measure among individuals who do not have AD. A high genetic correlation between these measures would suggest that a continuous measure of consumption may have a useful role in the discovery of genes contributing to dependence risk. METHODS Factor analysis of five alcohol use measures was used to create a measure of heaviness of alcohol consumption. Quantitative genetic analyses of interview data from the 1989 Australian Twin Panel (n = 6257 individuals; M = 29.9 years) assessed the genetic overlap between heaviness of consumption, DSM-IV AD symptoms, DSM-IV AD symptom clustering, and DSM-IV alcohol abuse. RESULTS Genetic influences accounted for 30%-51% of the variance in the alcohol measures and genetic correlations were .90 or higher for all measures, with the correlation between consumption and dependence symptoms among nondependent individuals estimated at .97 (95% confidence interval: .80-1.00). CONCLUSIONS Heaviness of consumption and AD symptoms have a high degree of genetic overlap even among nondependent individuals in the general population, implying that genetic influences on dependence risk in the general population are acting to a considerable degree through heaviness of use and that quantitative measures of consumption will likely have a useful role in the identification of genes contributing to AD.

Genetic contribution to individual variation in binocular rivalry rate

Binocular rivalry occurs when conflicting images are presented in corresponding locations of the two eyes. Perception alternates between the images at a rate that is relatively stable within individuals but that varies widely between individuals. The determinants of this variation are unknown. In addition, slow binocular rivalry has been demonstrated in bipolar disorder, a psychiatric condition with high heritability. The present study therefore examined whether there is a genetic contribution to individual variation in binocular rivalry rate. We employed the twin method and studied both monozygotic (MZ) twins (n = 128 pairs) who are genetically identical, and dizygotic (DZ) twins (n = 220 pairs) who share roughly half their genes. MZ and DZ twin correlations for binocular rivalry rate were 0.51 and 0.19, respectively. The best-fitting genetic model showed 52% of the variance in binocular rivalry rate was accounted for by additive genetic factors. In contrast, nonshared environmental influences accounted for 18% of the variance, with the remainder attributed to measurement error. This study therefore demonstrates a substantial genetic contribution to individual variation in binocular rivalry rate. The results support the vigorous pursuit of genetic and molecular studies of binocular rivalry and further characterization of slow binocular rivalry as an endophenotype for bipolar disorder.