Papers by Michelle Luciano
medRxiv (Cold Spring Harbor Laboratory), Feb 17, 2024
The ability to read is an important life skill and a major route to education. Individual differe... more The ability to read is an important life skill and a major route to education. Individual differences in reading ability are influenced by genetic variation, with a heritability of 0.66 for word reading, estimated by twin studies. Until recently, genomic investigations were limited by modest sample size. Here we use a multivariate genome-wide association study (GWAS) method, MTAG, to leverage summary statistics from two independent GWAS efforts, boosting power for analyses of reading ability; GenLang meta-analysis of word reading (N = 27 180) and the 23andMe, Inc., study of dyslexia (Ncases = 51 800, Ncontrols = 1 087 070). We increase effective sample size to N = 102 082, representing the largest genetic study of reading ability, to date. We identified 35 independent genome-wide significant loci, including 7 regions not previously reported. Single-nucleotide polymorphism (SNP) based heritability was estimated at 24%. We observed clear positive genetic correlations with cognitive and educational measures. Gene-set analyses implicated neuronal synapses and proneural glioblastoma pathways, further supported by enrichment of neuronally expressed genes in the developing embryonic brain. Polygenic scores of our multivariate results predicted between 2.29-3.50% of variance in reading ability in an independent sample, the National Child Development Study cohort (N = 6 410). Polygenic adaptation was examined using a large panel of ancient genomes spanning the last ~15k years. We did not find evidence of selection, suggesting that reading ability may not have been subject to recent selection pressure in Europeans. By combining existing datasets to improve statistical power, these results provide novel insights into the biology of reading. .
American Journal of Medical Genetics - Neuropsychiatric Genetics, Dec 27, 2011
Human longevity and personality traits are both heritable and are consistently linked at the phen... more Human longevity and personality traits are both heritable and are consistently linked at the phenotypic level. We test the hypothesis that candidate genes influencing longevity in lower organisms are associated with variance in the five major dimensions of human personality (measured by the NEO-FFI and IPIP inventories) plus related mood states of anxiety and depression. Seventy single nucleotide polymorphisms (SNPs) in six brain expressed, longevity candidate genes (AFG3L2, FRAP1, MAT1A, MAT2A, SYNJ1 and SYNJ2) were typed in over one thousand 70-year old participants from the Lothian Birth Cohort of 1936 (LBC1936). No SNPs were associated with the personality and psychological distress traits at a Bonferroni corrected level of significance (p < 0.0002), but there was an over-representation of nominally significant (p < 0.05) SNPs in the synaptojanin-2 (SYNJ2) gene associated with agreeableness and symptoms of depression. Eight SNPs which showed nominally significant association across personality measurement instruments were tested in an extremely large replication sample of 17 106 participants. SNP rs350292, in SYNJ2, was significant: the minor allele was associated with an average decrease in NEO agreeableness scale scores of 0.25 points, and 0.67 points in the restricted analysis of elderly cohorts (most aged > 60 years). Because we selected a specific set of longevity genes based on functional genomics findings, further research on other longevity gene candidates is warranted to discover whether they are relevant candidates for personality and psychological distress traits.
Molecular Psychiatry, Mar 6, 2019
Autosomal variants have successfully been associated with trait neuroticism in genome-wide analys... more Autosomal variants have successfully been associated with trait neuroticism in genome-wide analysis of adequately powered samples. But such studies have so far excluded the X chromosome from analysis. Here, we report genetic association analyses of X chromosome and XY pseudoautosomal single nucleotide polymorphisms (SNPs) and trait neuroticism using UK Biobank samples (N = 405,274). Significant association was found with neuroticism on the X chromosome for 204 markers found within three independent loci (a further 783 were suggestive). Most of the lead neuroticism-related X chromosome variants were located in intergenic regions (n = 397). Involvement of HS6ST2, which has been previously associated with sociability behaviour in the dog, was supported by single SNP and gene-based tests. We found that the amino acid and nucleotide sequences are highly conserved between dogs and humans. From the suggestive X chromosome variants, there were 19 nearby genes which could be linked to gene ontology information. Molecular function was primarily related to binding and catalytic activity; notable biological processes were cellular and metabolic, and nucleic acid binding and transcription factor protein classes were most commonly involved. X-variant heritability of neuroticism was estimated at 0.22% (SE = 0.05) from a full dosage compensation model. A polygenic X-variant score created in an independent sample (maximum N ≈ 7,300) did not predict significant variance in neuroticism, psychological distress, or depressive disorder. We conclude that the X chromosome harbours significant variants influencing neuroticism, and might prove important for other quantitative traits and complex disorders.
Psychological Medicine, Oct 2, 2019
Background. Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sough... more Background. Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression. Methods. We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu. Results. We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education. Conclusion. Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.
medRxiv (Cold Spring Harbor Laboratory), Apr 3, 2023
Frailty is a complex trait. Twin studies and a high-powered Genome Wide Association Study (GWAS) ... more Frailty is a complex trait. Twin studies and a high-powered Genome Wide Association Study (GWAS) conducted in the UK Biobank have demonstrated a strong genetic basis of frailty. The present study utilized summary statistics from this GWAS to create and test the predictive power of frailty polygenic risk scores (PRS) in two independent samples -the Lothian Birth Cohort 1936 (LBC1936) and the English Longitudinal Study of Ageing (ELSA) aged 67-84 years. Multiple regression models were built to test the predictive power of frailty PRS at five time points. Frailty PRS significantly predicted frailty at all-time points in LBC1936 and ELSA, explaining 2.1% (β = 0.15, 95%CI, 0.085-0.21) and 1.6% (β = 0.14, 95%CI, 0.10-0.17) of the variance, respectively, at age ~68/~70 years (p < 0.001). This work demonstrates that frailty PRS can predict frailty in two independent cohorts, particularly at early ages (~68/~70). PRS have the potential to be valuable instruments for identifying those at risk for frailty and could be important for controlling for genetic confounders in epidemiological studies.
Molecular Psychiatry, Jan 10, 2018
Pedigree-based analyses of intelligence have reported that genetic differences account for 50-80%... more Pedigree-based analyses of intelligence have reported that genetic differences account for 50-80% of the phenotypic variation. For personality traits these effects are smaller, with 34-48% of the variance being explained by genetic differences. However, molecular genetic studies using unrelated individuals typically report a heritability estimate of around 30% for intelligence and between 0 and 15% for personality variables. Pedigree-based estimates and molecular genetic estimates may differ because current genotyping platforms are poor at tagging causal variants, variants with low minor allele frequency, copy number variants, and structural variants. Using ~20,000 individuals in the Generation Scotland family cohort genotyped for ~700,000 single-nucleotide polymorphisms (SNPs), we exploit the high levels of linkage disequilibrium (LD) found in members of the same family to quantify the total effect of genetic variants that are not tagged in GWAS of unrelated individuals. In our models, genetic variants in low LD with genotyped SNPs explain over half of the genetic variance in intelligence, education, and neuroticism. By capturing these additional genetic effects our models closely approximate the heritability estimates from twin studies for intelligence and education, but not for neuroticism and extraversion. We then replicated our finding using imputed molecular genetic data from unrelated individuals to show that ~50% of differences in intelligence, and ~40% of the differences in education, can be explained by genetic effects when a larger number of rare SNPs are included. From an evolutionary genetic perspective, a substantial contribution of rare genetic variants to individual differences in intelligence, and education is consistent with mutation-selection balance.
Translational Psychiatry, Oct 18, 2011
The tendency to seek stimulating activities and intense sensations define excitement-seeking, a p... more The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N ¼ 7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P ¼ 2 Â 10 À8 ). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed a-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N ¼ 5105). The results provide insight into the genetics of excitementseeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders.
Nature Genetics, Dec 18, 2017
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Papers by Michelle Luciano