Generation Scotland


Research publications from 2018.

Genome-wide interaction study of a proxy for a stress-sensitivity and its prediction of major depressive disorder. Arnau-Soler, A., Adams, M. J., Scotland, G., Consortium, M. D. D., Hayward, C., Thomson, P. A. (2018). PLoS One.

Individual response to stress is correlated with neuroticism. Response to stress is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score.  The aim was to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significant SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.


Epigenetic signatures of starting and stopping smoking. McCartney, D. L., Stevenson, A. J., Hillary, R. F., Walker, R. M., Bermingham, M. L., Morris, S. W… Marioni, R. E. (2018). EBioMedicine. 

Exposure to cigarette smoke alters blood DNA at specific sites, typically at CpG dinucleotides, changing cytosine(C) to methylcytosine (meC), so called DNA methylation. 90 previously identified smoking-associated CpG sites, for over 4900 individuals in Generation Scotland, were assayed and analysed in the context of cigarette smoking behaviour.  The unsurprising finding was that ‘never’ smokers could be clearly distinguished from ‘ever’ smokers. The dramatic new findings were the ability to distinguish ‘light’ from ‘heavy’ smokers and that the epigenetic signature of heavy smokers typically lasted for more than 2 years after quitting. 


Genome-Wide and Abdominal MRI-Imaging Data Provides Evidence that a Genetically Determined Favourable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease and Hypertension. Ji, Y., Yiorkas, A.M., Frau, F., Mook-Kanamori., Staiger, H., Thomas, E.L… Yaghootkar, H (2018) Heart Disease and Hypertension.

Diabetes is linked to obesity, yet some individuals with higher than average body fat and BMI have lower risks of type 2 diabetes, heart disease, and hypertension. This study supported these findings and confirms 7 previous and 7 new genetic findings that go some way to explain this apparent conundrum. It seems that individuals carrying these genetic variants have higher subcutaneous fat, but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Genetic variants in the PPARG, GRB14, and IRS1 genes are associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes, whereas the ANKRD55 gene variant is paradoxically associated with higher visceral fat, but lower risk of type 2 diabetes. The likely mechanism is that these gene variants affect where in the body excess fat is stored. 


Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. Suri, P., Palmer, M. R., Tsepilov, Y, A., Freidin, M, B., Boer, C, G., Yau, M, S… Williams, F, M, K. (2018) PLOS Genetics.

Back pain is the number one cause of years lived with disability worldwide. GS asked participants to tell us about current and past problems with pain – where they were affected and how severely. This allowed us to join in a large study of 158,000 individuals of whom nearly 30,000 had chronic back pain. The study identified three novel genome-wide significant associations with chronic back pain, and suggests possible shared genetic mechanisms with other traits such as cartilage, osteoarthritis, lumbar disc degeneration, depression, and height/vertebral development. This is a good start, but even larger studies are required.


Epigenetic prediction of complex traits and death. McCartney, D. L., Hillary, R. F., Stevenson, A. J., Ritchie, S. J., Walker, R. M., Zhang, Q… Marioni, R. E. (2018) Genome Biology.

GS has one of the largest single cohort datasets of DNA methylation, which allows us to test whether methylation profiles can be used to predict a multitude of traits and diseases. The hope is that such predictors may be more accurate than self-reported phenotypes and could have clinical applications. This study tested ten modifiable health and lifestyle factors in a cohort of just over 5000 GS participants. We found that DNA methylation improved prediction of smoking, alcohol and various traits associated with obesity and heart disease over and above self-reports and genetic only tests.  


Genetic analysis of over one million people identifies 535 novel loci for blood pressure. Evangelou, E., Warren, H.R., Mosen-Ansorena, D., Mifsud, B., Pazoki, R., Gao, H… Caulfield, M.J. (2017) Nature Genetics.

The bigger the study, the greater the power to detect genetic associations with traits of interest. GS contributed along with many others to this genetic association analysis of blood pressure in over 1 million people through which 535 new genetic loci were identified. These findings provide new biological insights into blood pressure regulation and highlight shared genetic architecture between blood pressure and lifestyle exposures.


Comparison between high sensitivity cardiac troponin T and cardiac troponin I in a large general population cohort. Welsh, P., Preiss D., Shah, A.S.V., McAllister, D., Briggs, A., Boachie, C… Sattar, N. (2018) Clinical Chemistry.

GS collected a variety of biological samples, including serum, from a blood sample collected at the clinic visit (2006-2011). Serum can be tested for the presence of proteins that can act as indicators (biomarkers) of disease and response to treatment. For heart disease, the two most widely used biomarkers are troponin T and I. In the clinic, often one but not both are measured. Here, we tested both in nearly 20,000 GS samples, the largest yet study of samples collected from the general population. Interestingly, we found that the I and T forms are less closely correlated than previously thought. Moreover, elevated levels of the I form were more strongly associated with increased body mass index and blood pressure whilst the T form was more strongly associated predictive of diabetes. Importantly, although the cut offs currently used in clinical practice are broadly appropriate for men and women, this is not true beyond the age of 60 years.  


Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: A large Mendelian randomisation study. He, Y., Timofeeva, M., Farrington, S.M., Vaughan-Shaw, P., Svinti, V., Walker, M… Dunlop, M.G. (2018) BMC Medicine.

Studies suggest that vitamin D protects against colon cancer. This large study of over 10,000 cases and 30,000 controls tested genetic variants that have been associated with variation in circulating vitamin D levels and found a strong correlation in healthy controls. However, surprisingly there was no direct correlation with risk of colon cancer. 


Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Lee, J. J., Wedow, R., Okbay, A., Kong, E., Maghzian, O., Zacher, M…Cesarini, D. (2018) Nature Genetics. 

The bigger the study, the greater the power to detect genetic associations with traits of interest. GS contributed along with many others to this genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals. A staggering 1,271 independent genome-wide-significant genetic associations were identified. They implicate genes involved in brain-development processes and neuron-to-neuron communication. The combined (polygenic) genetic effect explains 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. 


The National Cancer Institute Cohort Consortium: an international pooling collaboration of 58 cohorts in 20 countries. Swerdlow, A.J., Harvey, C.E., Milne, R.L., Pottinger, C.A., Vachon, C.M., Wilkens, L.R... Winn, D.M (2018) Cancer Epidemiology, Biomarkers and Prevention.

Generation Scotland has pooled resources and data with 57 other cohorts to form the National Cancer Institute Cohort Consortium to study cancer epidemiology. This article describes the foundation of the Consortium; its structure, governance, and methods of working; the participating cohorts; publications; and opportunities. 


Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Prins, B.P.,  Mead T.J., Brody, J.A., Sveinbjornsson, G., Ntalla, I., Bihlmeyer, N.A… Jamshidi, Y. (2018) Genome Biology.

Using our exome chip data, combined with other cohorts to give a sample size of 78,000, a previously unrecognised gene, ADAMTS6, was shown to be associated with QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death.


DNA Methylation Signatures of Depressive Symptoms in Middle-aged and Elderly Persons: Meta-analysis of Multiethnic Epigenome-wide Studies. Jovanova, O., Nedeljkovic, I., Derek, S., Walker, R.M., Liu, C., Luciano, M… Amin, N. (2018) JAMA Psychiatry.

DNA methylation, a subtle modification of germline DNA sequence, determines which genes are switched on or off in different cell types and throughout life.  We added our GS data to the CHARGE consortium to form a study of 8,000 women with methylation analysis and measures of depression. Three methylation sites were found associated with depression. These sites pointed toward axon guidance as the common disrupted pathway in depression.


Analysis of shared heritability in common disorders of the brain. Brainstorm Consortium., Antilla, V., Builik-Sullivan, B., Finucane, H. K., Walter, R. K., Bras, J… Neale, B. M. (2018) Science.

This massive study under the umbrella of the Brainstorm Consortium, to which GS contributed, set out to test the extent of genetic overlap with and between psychiatric and neurologic disorders. With the caveat that we can only compare the genes sets that we currently know about, and which are incomplete for both classes of disorder, the answer to the question is relatively little overlap. The study did however show that the gene sets for one or other neurological condition are largely separate, whereas there is significant overlap between different psychiatric disorders, implying more of a diagnostic continuum than discrete, separate entities.


Investigating the relationship between DNA methylation age acceleration and risk factors for Alzheimer's disease. McCartney, D.L., Stevenson, A.J., Walker, R.M., Gibson, J., Morris, S.W., Campbell, A… Marioni, R.E. (2018) Alzheimer's and Dementia.

DNA methylation, a subtle modification of germline DNA sequence, determines which genes are switched on or off in different cell types and throughout life.  Age alone is the greatest risk factor for Alzheimer's disease. This GS study found significant associations between age acceleration, as measured by DNA methylation, and body mass index, total cholesterol to high-density lipoprotein cholesterol ratios, socioeconomic status, high blood pressure, and smoking behaviour. These are all factors that are associated with Alzheimer's disease and are potentially modifiable.  


Coding variants in NOD-like receptors: an association study on risk and survival of colorectal cancer. Huhn, S., da Silva Filho, M.I., Sanmuganantham, T., Pichulik T., Catalano, C., Pardini, B… Försti, A. (2018) PloS One.

In this study, Nod-like receptors in Czech cases of sporadic colon cancer were studied and evidence of genetic association found, these findings were not replicated in a Scottish sample (including GS) or an equivalent German study. 


Meta-analysis of exome array data identifies six novel loci for lung function. Jackson, V.E., Latourelle, J.C., Wain, L.V., Smith, A.V., Grove, M.L., Bartz, T.M… Tobin, M.D. (2018) Wellcome Open Research.

This study is an extension of previous collaborative work with the Spirometa consortium using the lung function data we collected and the genetic analysis we conducted in GS. Here, the focus was on detection of potentially damaging gene-coding variants detected by exome array chips.   Six new genetic associations were found. One was predicted to alter the function of the RPAP1 gene. Others were associated with genes that were plausibly associated with aspects of lung development, structure and function.


Using tree-based methods for detection of gene-gene interactions in the presence of a polygenic signal: simulation study with application to educational attainment in the Generation Scotland Cohort Study. Meijsen, J. j., Rammos, A., Campbell, A., Hayward, C., Porteous D. J., Deary, I. J., Marioni, R. E., Nicodemus, K. K. (2018) BioInformatics.

Genetic studies typically search for individual variants that affect the trait of interest (SNP-based association) or the sum of SNP-based effects (polygenic component). This study used an advanced computational approach (machine learning) to look for evidence of epistastic effects (interaction effects between genes). The study compared the strengths and weaknesses of alternative approaches on simulated data and preliminary evidence for epistatic effects on real data from GS in relation to educational attainment.    


Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. Feitosa, M. F., Kraja, A. T., Chasman, D. I., Sung, Y. J., Winkler, T. W., Ntalla, I… Levy, D. (2018) PLoS One.

GS was one of many cohorts contributing data to this study of 570,000 individuals for whom information on alcohol consumption, blood pressure and genetics was available.  The study identified 5 new and 49 previously known gene loci for blood pressure regulation in participants with European ancestry, and in multi-ancestry meta-analyses and 18 potentially novel loci for African ancestry samples. Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.


Multi-Ethnic Genome-wide Association Study for Atrial Fibrillation. Roselli, C., Chaffin, M. D., Weng, L. C., Aeschbacher, S., Ahlberg, G., Albert, C. M… Ellinor, P. T. (2018) Nature Genetics.  

Atrial fibrillation is the most common heart rhythm disorder, and is a leading cause of heart failure and stroke. It affects more than 33 million individuals worldwide. Genetic factors are important. This study combined all available previous genetic studies, including GS, more than half a million individuals in all, including over 65,000 with a diagnosis of atrial fibrillation. Nearly 100 genes were identified, of which 2/3 were newly discovered and some of which were restricted to specific populations. Some of the genes identified are involved in how the heart develops and beats.  This new knowledge may help the search for therapeutics.


DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders. Ryan, N. M., Lihm, J., Kramer, M., McCarthy, S., Morris, S. W., Arnau-Soler, A… Thomson, P. A. (2018) Molecular Psychiatry.

This study took a very detailed look at a well-studied Scottish family with many cases of schizophrenia and related major mental illness. A common feature is a damaged chromosome that halves the normal level of DISC1 gene expression. This gene is important for brain development and brain signalling. This study shows that the family is affected not only by DISC1, but up to four other genes that are thought to modify the severity of symptoms. The Generation Scotland samples helped independently confirm the effect of these new findings on the risk of depression.


European Prevention of Alzheimer’s Dementia (EPAD) Registry: recruitment and pre-screening approach for a longitudinal cohort and prevention trials. Vermunt, L., Veal, C. D., ter Meulen, L., Chrysostomou, C., van der Flier, W., Frisoni, G. B. (2018) Alzheimer's and Dementia.

Generation Scotland participants were recruited through GP practices and there were no criteria set for inclusion or exclusion, except to be willing and well enough to take part at the time of recruitment. The hope always was that new investigators with an interest in a specific condition would come to us and be able to invite GS members to participate in add on studies. This paper describes one such, aimed at dementia prevention. Already several GS participants have signed up to help with this important study.


Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Davies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, D. W… Deary, I. J. (2018) Nature Communications.

This was a major study of 300,000 participants, including Generation Scotland data alongside several other cohorts as part of the CHARGE consortium, plus COGENT and UK Biobank. 148 independent genetic associations were found with respect to general cognitive function, a sharp increase on previous studies. Amongst the new findings were overlaps with genetics risk factors known to be involved in neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Overall, there was genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity.  Although this study marks a significant advance, a substantial proportion of the overall contribution of genetics remains hidden. 


Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder. Li, X., Luo, Z., Gu, C., Hall, L. S., McIntosh, A. M., Zeng, Y… The 23andMe Research Team7 (2018) Neuropsychopharmacology. 

After a slow start, rapid progress is being made to identify genetic risk factors for depression and Generation Scotland is playing an important role. Here, we help to identify three new gene regions and two specific genes, FBXL4 and RSRC1 that were expressed at significantly higher levels in brains of patients with depression than in controls. The brain samples and expression studies came from a previously published study, not from Generation Scotland participants.  


Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A… the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2018) Nature Genetics. 

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. Generation Scotland was one of seven cohorts with detailed genetic and clinical information which when combined summed to over 135,000 cases and 344,000 controls. The study identified 44 genetic loci that were significantly linked to risk of MDD. These genetic findings pointed to particular brain regions being important and included known targets of antidepressants used in clinical practice. There were findings in common too with genes known to influences the risk of schizophrenia, a more severe form of mental illness, and to other brain and body traits. It is important to note that we all carry lesser or greater numbers of genetic risk factors for major depression. The large number of genes now identified provides a way forward to better understanding how these combine with lifestyle and other factors, such as stressful life events, to increase or protect against risk and response to treatment.


Association of opioid prescribing practices with chronic pain and benzodiazepine co-prescription: a primary care data linkage study. Torrance, N., Mansoor, R., Wang, H., Gilbert, S., Macfarlane, G.J., Serpell, M., Baldacchino, A… Colvin, L. (2018) British Jounal of Anaesthesia.

Opiods, such as methadone and pethidine, have a vital role to play in pain management, but the risk of addiction is a concern. There is a worrying increase in the level of opioid prescription worldwide. This Generation Scotland study took advantage of our ability to link history of past and present pain and baseline to prescribing data. The study found that there were regional and sociodemographic variation across Scotland in opioid prescribing. Prescribing is on the increase (18% of the population in 2012). Co-prescription with benzodiazepine was also high despite the risk of dangerous drug interactions.


MSR1 repeats modulate gene expression and affect risk of breast and prostate cancer. Rose, A.M., Krishan, A., Chakarova, C.F., Moya, L, Chambers, S.K., Hollands, M…Bhattacharya. (2018) Annals of Ocology. Volume 29, Issue 5, Pages 1292-1303.

The human genome is peppered with short segments of DNA sequence that are repeated in number and which vary between individuals in the number of copies carried. It is thought the number of copies an individual carries can affect the level of adjacent gene expression. This study used Generation Scotland samples as controls to test if this was true for one such repeat, MSR1, and risk of breast or prostate cancer. The rare 9-copy version had a strong effect on breast cancer risk compared with the common 11-copy version for both types of cancer.


Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland: Scottish Family Health Study. Meijsen, J.J., Campbell, A., Hayward, C., Porteous, D.J., Deary, I.J., Marioni, R.E.,  Nicodemus, K.K. (2018) Translational Psychiatry. 8(1):63.

This is an example of a study that relied entirely upon Generation Scotland data. We show that major depressive disorder is associated with lower levels of thinking skills (cognition) and is more so in those with recurrent, rather than single, episodes of depression. The effects are small but significant and shared between many genes.


Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Pardiñas, A.F., Holmans, P., Pocklington, A.J., Escott-Price, V., Ripke, S., Carrera, N… CRESTAR Consortium. (2018). Nature Genetics. 50(3):381-389

Remarkable progress has been made in recent years to identify some of the common genetic factors that affect risk of developing schizophrenia. This study adds to that knowledge and understanding in three ways: first, by adding 50 more gene loci to the previously known list, making 145 in total; second, by looking at the biological roles played by this list of genes, showing that a high proportion are involved in the wiring of the brain and the communication between one neuron to another; and third, that this gene set is enriched for those that are under strong selective pressure. This last observation is perhaps the more significant new finding and at first sight, counter intuitive, as one might expect genes for schizophrenia to be removed from the population because those affected are less likely to have children and pass on their genes.


Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference. Corbin, L.J., Tan, V.Y., Hughes, D.A., Wades, K.H., Paul, D.S., Tansey, K.E…. Timpson, N.J. (2018) Nature Communications. 

This review paper highlights Generation Scotland as one of limited set of UK cohorts where it is possible to conduct statistical powerful recall-by-genotype studies that minimise confounding and mimic randomised control trials by comparing the outcome of having or not having a specific genetic variant on a defined disorder or trait.  


Genetic and environmental contributions to psychological resilience and coping. Navrady, L, B., Zeng, Y., Clarke, T-K, Adams, M, J., Howard, D, M., Deary, I, J., McIntosh, A, M. (2018) Wellcome Open Research.

This Generation Scotland / STRADL study looked at how genetics and shared environment affect coping styles and found that genetic factors that increase negative emotionality also lead to decreased resilience. However only a fraction of the individual differences in coping were explained, emphasising the need for larger sample sizes.


A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. Sung, Y. J., Winkler, T. W., de Las Fuentes, L., Bentley, A.R., Brown, M.R., Kraja, A.T… Chasman, D.I. (2018). American Journal of Human Genetics.

GS contributed data to this massive study of 600,000 individuals for genetic association with systolic and diastolic blood pressure. 66 new genetic findings were made and 56 known findings confirmed. The genes identified can now be studied for how they function in blood pressure regulation.


Age at menarche and cardiometabolic health: a sibling analysis in the Scottish Family Health Study. Bihlmeyer, N.A., Brody, J.A., Smith, A.V., Waren, H.R., Lin, H, Isaacs, A… Arking, D.E. (2018). Journal of the American Heart Association. 2018;7:e007780.

This study of women and more particularly sisters in GS was undertaken to try to resolve the conflicting evidence for the relationship between age at menarche (first menstrual bleeding) and later cardiovascular disease. The study found weak evidence of associations between later menarche and lower body mass index, waist circumference, and blood pressure. Adult body mass index seemed to account for the associations seen with other cardiovascular risk factors. 


ExomeChip-wide analysis of 95,626 individuals identifies 10 novel loci associated with QT and JT intervals. Bihlmeyer, N.A., Brody, J.A., Smith, A.V., Waren, H.R., Lin, H, Isaacs, A… Arking, D.E. (2018). Circulation: Genomic and Precision Medicine. 2018;11:e001758.

GS contributed exome chip data to this study of over 95,000 participants for whom ECG measures were also available. The study found 10 previously unreported genetic loci that modulate the QT and JT interval duration, important features of heart function and predictors of sudden cardiac arrest that can be extracted from ECG measures. 


A genome-wide meta-analysis of stratified  depression in Generation Scotland and UK Biobank. Hall, L.S., Adams, M.J., Arnau-Soler, A., Clarke Toni-Kim., Howard, D.M., Zeng, Y… McIntosh, A.M. (2018). Translational Psychiarty 8(9). 

This study combined data from GS with the first stage data release from the UK Biobank to look for evidence of genetic association for major depressive disorder. One purpose of the study was to test whether it was more effective to be specific about the type of depression (single or recurrent, early or late onset, male or female) or group all cases together. The findings were somewhat equivocal but it is hard to argue against maximising sample sizes.


Genomic analysis of family data reveals additional genetic effects on intelligence and personality. Hill, D. W., Arslan, R. C., Xia, C., Luciano, M., Amador, C., Navaro, P., … Penke, L. (2018). Molecular Psychiatry.

This study takes advantage of the family structure in GS to provide a better estimate of the overall genetic variance in intelligence, education, and neuroticism. Current estimates for case-control studies are lower than for twin studies. The family structure helps capture the unseen contribution of rare variants that are not directly typed in GWAS studies. The genetic variance measured, in this way, closely approximates that which is estimated in twin studies. It suggests that both rare and common genetic variants contribute to individual differences in intelligence and education.