BackgroundEpigenetic scores (EpiScores) can provide blood-based biomarkers of lifestyle and disea... more BackgroundEpigenetic scores (EpiScores) can provide blood-based biomarkers of lifestyle and disease risk. Projecting a new individual onto a reference panel would aid precision medicine and risk communication but is challenging due to the separation of technical and biological sources of variation with array data. Normalisation methods can standardize data distributions but may also remove population-level biological variation.MethodsWe compared two independent birth cohorts (Lothian Birth Cohorts of 1921 and 1936 – nLBC1921= 387 and nLBC1936= 498) with DNA methylation assessed at the same chronological age (79 years) and processed in the same lab but in different years and experimental batches. We examined the effect of 15 normalisation methods on a BMI EpiScore (trained in an external cohort of 18,413 individuals) when the cohorts were normalised separately and together.ResultsThe BMI EpiScore explained a maximum variance of R2=24.5% in BMI in LBC1936 after SWAN normalisation. Alt...
Data supporting the paper Hillary et al. "Genetic and epigenetic architectures of neurologic... more Data supporting the paper Hillary et al. "Genetic and epigenetic architectures of neurological protein biomarkers in the Lothian Birth Cohort 1936" (In submission). Specifically GWAS proteins.
ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in larg... more ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10−8; and LINC00539/ZDHHC20, p = 5.82 × 10−9. Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follo...
Identifying genetic variants influencing human brain structures may reveal new biological mechani... more 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…
Objective: We explored genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in l... more Objective: We explored genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely small sub-cortical BI (SSBI), in eighteen population-based cohorts (N=20,949) from five ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in seven population-based cohorts (N=6,862, 1,483 with BI, 630 with SBBI), and tested associations with related phenotypes including ischemic stroke and pathologically-defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, P=1.77×10-8 and LINC00539/ZDHHC20, P=5.82×10-9. Both have been associated with blood pressure (BP) related phenotypes, but did not replicate in the smaller follow-up sample nor show associations with related phenotypes. Age and sex-adjusted associations with BI and SSBI were observed for BP traits (P-value for BI, P[BI]=9.38×10-25; P[SSBI]=5.23×10-14 for hypertension), smoking (P[BI]=4.4×10-10; P[SSBI]=1.2×10-4), diabetes (P[BI]=1.7×10-8; P[SSBI]=2.8×10-3), previous cardiovascular disease (P[BI]=1.0×10-18; P[SSBI]=2.3×10-7), stroke (P[BI]=3.9×10-69; P[SSBI]=3.2×10-24), and MRI-defined white matter hyperintensity burden (P[BI]=1.43×10-157; P[SSBI]=3.16×10-106), but not with body-mass-index or cholesterol. GRS of BP traits were associated with BI and SSBI (P≤0.0022), without indication of directional pleiotropy. Conclusions: In this multi-ethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI
The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of ch... more The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
Male pattern baldness can have substantial psychosocial effects, and it has been phenotypically l... more Male pattern baldness can have substantial psychosocial effects, and it has been phenotypically linked to adverse health outcomes such as prostate cancer and cardiovascular disease. We explored the genetic architecture of the trait using data from over 52,000 male participants of UK Biobank, aged 40-69 years. We identified over 250 independent novel genetic loci associated with severe hair loss. By developing a prediction algorithm based entirely on common genetic variants, and applying it to an independent sample, we could discriminate accurately (AUC = 0.82) between those with no hair loss from those with severe hair loss. The results of this study might help identify those at the greatest risk of hair loss and also potential genetic targets for intervention.
Previous reports of altered grey and white matter structure in Major Depressive Disorder (MDD) ha... more Previous reports of altered grey and white matter structure in Major Depressive Disorder (MDD) have been inconsistent. Recent meta-analyses have, however, reported reduced hippocampal grey matter volume in MDD and reduced white matter integrity in several brain regions. The use of different diagnostic criteria, scanners and imaging sequences may, however, obscure further anatomical differences. In this study, we tested for differences in subcortical grey matter volume (n=1157) and white matter integrity (n=1089) between depressed individuals and controls in the subset of 8590 UK Biobank Imaging study participants who had undergone depression assessments. Whilst we found no significant differences in subcortical volumes, significant reductions were found in depressed individuals versus controls in global white matter integrity, as measured by fractional anisotropy (FA) (β=-0.182, p=0.005). We also found reductions in FA in association/commissural fibres (β=-0.184, pcorrected=0.010) a...
Differences in general cognitive function have been shown to be partly heritable and to show gene... more Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with a several psychiatric and physical disease states. However, to date few single nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium and UK Biobank, to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regi...
Educational attainment is strongly influenced by social and other environmental factors, but gene... more Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environment...
Individuals with lower socio-economic status (SES) are at increased risk of physical and mental i... more Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses and tend to die at an earlier age [1-3]. Explanations for the association between SES and health typically focus on factors that are environmental in origin [4]. However, common single nucleotide polymorphisms (SNPs) have been found collectively to explain around 18% (SE = 5%) of the phenotypic variance of an area-based social deprivation measure of SES [5]. Molecular genetic studies have also shown that physical and psychiatric diseases are at least partly heritable [6]. It is possible, therefore, that phenotypic associations between SES and health arise partly due to a shared genetic etiology. We conducted a genome-wide association study (GWAS) on social deprivation and on household income using the 112,151 participants of UK Biobank. We find that common SNPs explain 21% (SE = 0.5%) of the variation in social deprivation and 11% (SE = 0.7%) in household income. Two independent...
Background Poorer self-rated health (SRH) predicts worse health outcomes, even when adjusted for ... more Background Poorer self-rated health (SRH) predicts worse health outcomes, even when adjusted for objective measures of disease at time of rating. Twin studies indicate SRH has a heritability of up to 60% and that its genetic architecture may overlap with that of personality and cognition. Methods We carried out a genome-wide association study (GWAS) of SRH on 111 749 members of the UK Biobank sample. Univariate genome-wide complex trait analysis (GCTA)-GREML analyses were used to estimate the proportion of variance explained by all common autosomal SNPs for SRH. Linkage Disequilibrium (LD) score regression and polygenic risk scoring, two complementary methods, were used to investigate pleiotropy between SRH in UK Biobank and up to 21 health-related and personality and cognitive traits from published GWAS consortia. Results The GWAS identified 13 independent signals associated with SRH, including several in regions previously associated with diseases or disease-related traits. The st...
General cognitive function predicts psychiatric illness across the life course. This study examin... more General cognitive function predicts psychiatric illness across the life course. This study examines the role of pleiotropy in explaining the link between cognitive function and psychiatric disorder. We used two large genome-wide association study data sets on cognitive function-one from older age, n = 53,949, and one from childhood, n = 12,441. We also used genome-wide association study data on educational attainment, n = 95,427, to examine the validity of its use as a proxy phenotype for cognitive function. Using a new method, linkage disequilibrium regression, we derived genetic correlations, free from the confounding of clinical state between psychiatric illness and cognitive function. We found a genetic correlation of .711, (p = 2.26e-12) across the life course for general cognitive function. We also showed a positive genetic correlation between autism spectrum disorder and cognitive function in childhood (rg = .360, p = .0009) and for educational attainment (rg = .322, p = 1.37...
Proceedings of the National Academy of Sciences of the United States of America, Jan 23, 2014
We identify common genetic variants associated with cognitive performance using a two-stage appro... more 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 ...
BackgroundEpigenetic scores (EpiScores) can provide blood-based biomarkers of lifestyle and disea... more BackgroundEpigenetic scores (EpiScores) can provide blood-based biomarkers of lifestyle and disease risk. Projecting a new individual onto a reference panel would aid precision medicine and risk communication but is challenging due to the separation of technical and biological sources of variation with array data. Normalisation methods can standardize data distributions but may also remove population-level biological variation.MethodsWe compared two independent birth cohorts (Lothian Birth Cohorts of 1921 and 1936 – nLBC1921= 387 and nLBC1936= 498) with DNA methylation assessed at the same chronological age (79 years) and processed in the same lab but in different years and experimental batches. We examined the effect of 15 normalisation methods on a BMI EpiScore (trained in an external cohort of 18,413 individuals) when the cohorts were normalised separately and together.ResultsThe BMI EpiScore explained a maximum variance of R2=24.5% in BMI in LBC1936 after SWAN normalisation. Alt...
Data supporting the paper Hillary et al. "Genetic and epigenetic architectures of neurologic... more Data supporting the paper Hillary et al. "Genetic and epigenetic architectures of neurological protein biomarkers in the Lothian Birth Cohort 1936" (In submission). Specifically GWAS proteins.
ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in larg... more ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10−8; and LINC00539/ZDHHC20, p = 5.82 × 10−9. Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follo...
Identifying genetic variants influencing human brain structures may reveal new biological mechani... more 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…
Objective: We explored genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in l... more Objective: We explored genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely small sub-cortical BI (SSBI), in eighteen population-based cohorts (N=20,949) from five ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in seven population-based cohorts (N=6,862, 1,483 with BI, 630 with SBBI), and tested associations with related phenotypes including ischemic stroke and pathologically-defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, P=1.77×10-8 and LINC00539/ZDHHC20, P=5.82×10-9. Both have been associated with blood pressure (BP) related phenotypes, but did not replicate in the smaller follow-up sample nor show associations with related phenotypes. Age and sex-adjusted associations with BI and SSBI were observed for BP traits (P-value for BI, P[BI]=9.38×10-25; P[SSBI]=5.23×10-14 for hypertension), smoking (P[BI]=4.4×10-10; P[SSBI]=1.2×10-4), diabetes (P[BI]=1.7×10-8; P[SSBI]=2.8×10-3), previous cardiovascular disease (P[BI]=1.0×10-18; P[SSBI]=2.3×10-7), stroke (P[BI]=3.9×10-69; P[SSBI]=3.2×10-24), and MRI-defined white matter hyperintensity burden (P[BI]=1.43×10-157; P[SSBI]=3.16×10-106), but not with body-mass-index or cholesterol. GRS of BP traits were associated with BI and SSBI (P≤0.0022), without indication of directional pleiotropy. Conclusions: In this multi-ethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI
The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of ch... more The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
Male pattern baldness can have substantial psychosocial effects, and it has been phenotypically l... more Male pattern baldness can have substantial psychosocial effects, and it has been phenotypically linked to adverse health outcomes such as prostate cancer and cardiovascular disease. We explored the genetic architecture of the trait using data from over 52,000 male participants of UK Biobank, aged 40-69 years. We identified over 250 independent novel genetic loci associated with severe hair loss. By developing a prediction algorithm based entirely on common genetic variants, and applying it to an independent sample, we could discriminate accurately (AUC = 0.82) between those with no hair loss from those with severe hair loss. The results of this study might help identify those at the greatest risk of hair loss and also potential genetic targets for intervention.
Previous reports of altered grey and white matter structure in Major Depressive Disorder (MDD) ha... more Previous reports of altered grey and white matter structure in Major Depressive Disorder (MDD) have been inconsistent. Recent meta-analyses have, however, reported reduced hippocampal grey matter volume in MDD and reduced white matter integrity in several brain regions. The use of different diagnostic criteria, scanners and imaging sequences may, however, obscure further anatomical differences. In this study, we tested for differences in subcortical grey matter volume (n=1157) and white matter integrity (n=1089) between depressed individuals and controls in the subset of 8590 UK Biobank Imaging study participants who had undergone depression assessments. Whilst we found no significant differences in subcortical volumes, significant reductions were found in depressed individuals versus controls in global white matter integrity, as measured by fractional anisotropy (FA) (β=-0.182, p=0.005). We also found reductions in FA in association/commissural fibres (β=-0.184, pcorrected=0.010) a...
Differences in general cognitive function have been shown to be partly heritable and to show gene... more Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with a several psychiatric and physical disease states. However, to date few single nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium and UK Biobank, to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regi...
Educational attainment is strongly influenced by social and other environmental factors, but gene... more Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environment...
Individuals with lower socio-economic status (SES) are at increased risk of physical and mental i... more Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses and tend to die at an earlier age [1-3]. Explanations for the association between SES and health typically focus on factors that are environmental in origin [4]. However, common single nucleotide polymorphisms (SNPs) have been found collectively to explain around 18% (SE = 5%) of the phenotypic variance of an area-based social deprivation measure of SES [5]. Molecular genetic studies have also shown that physical and psychiatric diseases are at least partly heritable [6]. It is possible, therefore, that phenotypic associations between SES and health arise partly due to a shared genetic etiology. We conducted a genome-wide association study (GWAS) on social deprivation and on household income using the 112,151 participants of UK Biobank. We find that common SNPs explain 21% (SE = 0.5%) of the variation in social deprivation and 11% (SE = 0.7%) in household income. Two independent...
Background Poorer self-rated health (SRH) predicts worse health outcomes, even when adjusted for ... more Background Poorer self-rated health (SRH) predicts worse health outcomes, even when adjusted for objective measures of disease at time of rating. Twin studies indicate SRH has a heritability of up to 60% and that its genetic architecture may overlap with that of personality and cognition. Methods We carried out a genome-wide association study (GWAS) of SRH on 111 749 members of the UK Biobank sample. Univariate genome-wide complex trait analysis (GCTA)-GREML analyses were used to estimate the proportion of variance explained by all common autosomal SNPs for SRH. Linkage Disequilibrium (LD) score regression and polygenic risk scoring, two complementary methods, were used to investigate pleiotropy between SRH in UK Biobank and up to 21 health-related and personality and cognitive traits from published GWAS consortia. Results The GWAS identified 13 independent signals associated with SRH, including several in regions previously associated with diseases or disease-related traits. The st...
General cognitive function predicts psychiatric illness across the life course. This study examin... more General cognitive function predicts psychiatric illness across the life course. This study examines the role of pleiotropy in explaining the link between cognitive function and psychiatric disorder. We used two large genome-wide association study data sets on cognitive function-one from older age, n = 53,949, and one from childhood, n = 12,441. We also used genome-wide association study data on educational attainment, n = 95,427, to examine the validity of its use as a proxy phenotype for cognitive function. Using a new method, linkage disequilibrium regression, we derived genetic correlations, free from the confounding of clinical state between psychiatric illness and cognitive function. We found a genetic correlation of .711, (p = 2.26e-12) across the life course for general cognitive function. We also showed a positive genetic correlation between autism spectrum disorder and cognitive function in childhood (rg = .360, p = .0009) and for educational attainment (rg = .322, p = 1.37...
Proceedings of the National Academy of Sciences of the United States of America, Jan 23, 2014
We identify common genetic variants associated with cognitive performance using a two-stage appro... more 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 ...
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