Generation Scotland

2019

Research publications from 2019.

The role of neuroticism in self-harm and suicidal ideation: results from two UK population-based cohorts. Hafferty, J. D., Navrady, L. B., Adams, M. J., Howard, D. M., Campbell, A. I., Whalley, H. C… McIntosh, A. M. (2019). Social Psychiatry and Psychiatric Epidemiology. 

One in fifty GS participants report self-harming, a behaviour that is strongly associated with suicide and thought of committing suicide. This study found a strong association between neuroticism and both self-harm and suicidal ideation. This has implications for how those at risk might be identified and the risk of progressing to self-harm or suicide reduced.

 

Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Law, P. J., Timofeeva, M., Fernandez-Rozadilla, C., Broderick, P., Studd, J., Fernandez-Tajes, J… Dunlop, M. G. (2019). Nature Communications 10(1):2154. 

GS provides control data for this study that found evidence for 31 new genetic risk factors for colon cancer.

 

Cardiac Troponin T and Troponin I in the general population: contrasting genetic determinants and outcomes. Welsh, P., Preiss, D., Hayward, C., Shah, A. S. V., McAllister, D., Briggs, A… Sattar N. (2019). Circulation.

Troponin I and T are proteins that can be accurately measured in the blood. One or both are routinely used to assess heart damage. This study measured Troponin I and T in 20,000 GS participants. The findings confirmed high predictive value for heart disease, but only I predicted non-cardiovascular disease death. These findings should influence the choice of test according to the clinical circumstances. 

 

Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits. Hafferty, J. D., Navrady, L. B., Adams, M. J., Howard, D. M., Campbell, A. I., Whalley, H. C… McIntosh, A. M. (2019). Social Psychiatry and Psychiatric Epidemiology. 

As a rule of thumb, most traits are influenced by multiple genetic variants, each of small effect, and reciprocally, most genetic risk variants affect multiple traits. This raises statistical and methodological challenges. In psychology, structural equation modelling is a long-favoured method to analyse multivariate traits. This study describes and applies an extension that allows genetic correlations to be incorporated. Genomic structural equation modelling (genomic SEM) can be used to model multivariate genetic associations among phenotypes, identify variants with effects on general dimensions of cross-trait liability, calculate more predictive polygenic scores and identify loci that cause divergence between traits. The approach was tested on five psychiatric traits measured in GS. 

 

Insulin resistance: Genetic associations with depression and cognition in population based cohorts. Frangou, S., Shirali, M., Adams, M. J., Howard, D. M., Gibson, J., Hall, L. S… McIntosh, A. M. (2019). Experimental Neurology 316: 20-26.

Insulin resistance, the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction, the causal factors are unknown. This study used genetic information from UK Biobank and GS to test for causal genetic effects. Although the GS data provided some evidence, this was not confirmed in the UK Biobank.  

 

Assessment of Dried Blood Spots for DNA Methylation Profiling. Walker, R. M., MacGillivray, L., McCafferty, S., Wrobel, N., Murphy, L., Kerr, S. M… Evans, K. L. (2019). Wellcome Open Research.

When we extracted whole blood for genetic studies in GS participants, we spotted drops onto filter paper for QC purposes. This allowed us to go back to the dried blood spots 7-13 years later to see how well they worked compared to fresh blood DNA for studies of methylation. The results were very encouraging. This means we can consider collecting blood samples this way in future, instead of with a needle and syringe in a clinic. This would open the door to participants living remotely. It also suggests that it might be possible to anchor our future studies at birth by analysing neonatal dried blood spots (Guthrie cards) that are used to check for rare metabolic or inherited diseases and then stored long-term. 

 

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies novel loci associated with serum lipids. Bentley, A. R., Sung, Y. J., Brown, M. R., Winkler, T. W., Kraja, A. T., Ntalla, I… Cupples, L. A. (2019). Nature Genetics 51(4): 636-648.

GS was one of several cohorts of different ancestries that had genetic data, information on smoking behaviour and measures of lipids. This allowed the authors to identify 13 new genetic loci that affect lipid levels and are influenced by smoking status. 

 

Parent of origin genetic effects on methylation in humans are unexpectedly common and influence complex trait variation. Zeng, Y., Amador, C., Xia, C., Marioni, R., Sproul, D., Walker, R. M… Haley, C. S. (2019). Nature Communciations 10: 1383.

When the expression of an allele is influenced by whether it has been inherited from the mother or the father, we call this a parent-of-origin effect. They are often associated with early growth and metabolism and influenced by the genetic modification of DNA in the form of methylation. This study used the genome-wide methylation data available in GS to discover 171 new sites showing parent-of-origin effect, an increase of about a third on previous studies. 

 

Personalized Medicine and the Power of Electronic Health Records. Abul Husn, N. S and Kenny, E. E. (2019). Cell 177(1):58-59.

This important review into the current state-of-play and future opportunities for research that uses electronic health record linkage features GS as one of the cohorts leading the way forward.

 

Genetic contributions to two special factors of neuroticism are associated with affluence, higher intelligence, better health, and longer life. Hill, D. W., Weiss, A., Liewald, D. C., Davies, G., Porteous, D. J.,  Hayward, C… Deary, I. J. (2019) Molecular Psychiatry.

Neuroticism, the tendency to experience negative emotions, has a strong genetic component. High levels of neuroticism are associated with poorer health, social standing and intelligence. But it’s a complicated relationship. Questionnaires that measure neuroticism can be broken down to measure levels of anxiety/tension or of worry/vulnerability. Intriguingly, we find that genetic variants associated with high levels of anxiety/tension and with high levels of worry/vulnerability are actually associated with higher social standing and higher intelligence, with better self-rated health and longer life. It will be important to study the genetic basis of these protective aspects of neuroticism in more detail.

 

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium. Polimanti, R., Peterson, R. E., Ong, J-S., MacGregor, S., Edwards, A. C., Clarke, T-K… Derks, E. M. (2019). Psychological Medicine 1-9.

GS is a fully signed up member for the Psychiatric Genomics Consortium studies of depression. This study found evidence to show that individuals carrying a higher number of genetic risk factors for depression were also predisposed to alcohol dependence. 

 

An epigenetic score for BMI based on DNA methylation correlates with poor physical health and major disease in the Lothian Birth Cohort. Hamilton, O. K. L., Zhang, Q., McRae, A. F., Walker, R. M., Morris, S. W., Redmond, P… Marioni, R. E. (2019). International Journal of Obesity.

This study used information from Generation Scotland (~2,500 sample) on the epigenetic contribution to body mass index (BMI) to test in an independent cohort, the Lothian Birth Cohort 1936 (>400 samples), for the impact on BMI itself and other measures of ill health. The study found that the epigenetic BMI score slower walking, poorer lung function, lower health-related quality of life, physical inactivity, and greater social deprivation. The epigenetic BMI score was also associated with higher blood lipids and blood pressure, and more type 2 diabetes and cardiovascular disease. Combining direct measures of BMI with the epigenetic BMI score improved prediction over that observed with either one measure.

 

The influence of X chromosome variants on trait neuroticism. Luciano, M., Davies, G., Summers, K. M., Hill, D., Hayward, C., Liewald, D. C… Deary, I. J. (2019). Molecular Psychiatry.

Over the last decade genome-wide association studies have proliferated and led to many advances in our genetic understanding of a very wide range of human traits and diseases. Yet only a small minority of such studies have directly tested the genetic contributions of the X and Y (sex) chromosomes.  It becomes important to do so if there is evidence of a sex-difference for the trait of interest, as is the case for neuroticism. This study used the UK Biobank cohort to test and the Generation Scotland cohort to confirm evidence for the influence of gene variants on the X chromosome.  Several genetic signals were found, the most interesting of which was for a gene called HS6ST2, which has been previously associated with sociability behaviour dogs. The overall conclusion was that the X chromosome harbours significant genetic variants influencing neuroticism. Quite possibly, this will be true for many other human traits and disorders, where the incidence or manifestation differs between males and females.

 

Pharmaco-epidemiology of Antidepressant Exposure in a UK Cohort Record-Linkage Study. Hafferty, J. D., Wigmore, E. M., Howard, D. M., Adams, M. J., Clarke, T-K., Campbell, A. I…. McIntosh, A. M. (2019). Journal of Psychopharmacology.

Concern has been raised around a sharp upturn in the number of antidepressants currently being prescribed. We were able to look at this in more detail thanks to the comprehensive prescribing data available in Scotland. 28% of GS participants were prescribed an antidepressant between 2012-2016. There was a 36% increase in prescribing between 2010 and 2016. The majority prescribed antidepressants had depression for over 9 months and generally stuck to their medication. Our findings of longer length of episodes and good adherence go some way towards explain the rise in antidepressant prescriptions.

 

New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries. Shrine, N., Guyatt, A. L., Erzurumluoglu, M., Jackson, V. E., Hobbs, B. D., Melbourne, C. A… Wain, L. V. (2019). Nature Genetics.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). This is the latest in a series of papers that use GS data together with many other studies to explore the genetic determinants of COPD. By studying over 400,000 individuals of European ancestry, 279 lung function genetic signals were found, 139 of which are new. In combination, these variants strongly predict COPD in independent populations, whether smokers or not. Importantly, the gene findings pointed to biological pathways with known and potential drug targets for COPD, which could improve future preventive and therapeutic strategies for COPD.

 

Conditioning on a collider does not explain the relationship between lower neuroticism and premature mortality in Gale et al. (2017): A reply to Richardson, Davey Smith, and Munafó (2018). Weiss, A., Gale, C. R., Čukić, I., Batty, D. G., McIntosh, A. M., Deary, I. J. (2019). Psychological Science.

Scientific research findings are sometimes so clear cut that there is only one plausible interpretation, but that is not always the case. Debate, clarification and re-evaluation may be warranted. This paper is one such example. The paper summarises the response by the original authors to a query raised regarding the possible reason for the observed relationship between lower neuroticism and premature mortality.  

 

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Justice, A. E., Karaderi, T., Highland, H. M., Young, K. L., Graff, M., Lu, Y… Lindgren, C. M. (2019). Nature Genetics.

GS was part of this large multi-cohort consortium study that found 15 common and 9 low frequency genetic variants affecting body-fat distribution. When the expression of two of these genes were experimentally reduced in fruit flies their fat levels increased, consistent with the genetic findings in people. 

 

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Howard, D. M., Adams, M. J., Clarke, T-K., Hafferty, J. D., Gibson, J., Shirali, M… McIntosh, A (2019). Nature Neuroscience.

Major depression is a debilitating psychiatric illness that affects 1 in 6 in their lifetime. This study, led by GS researchers and in partnership with the PGC and 23andme, is, by far, the largest and most successful genetic study of depression. 102 independent variants, 269 genes, and 15 gene sets associated with depression were identified. These genes and gene pathways were associated with synaptic structure and neurotransmission. They also point to the importance of prefrontal brain regions. The field now has a rich set of genetic leads to follow up on that should help understanding etiology and developing new treatment approaches.

 

Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland. Arnau-Soler, A., Adams, M. J., Clarke, T-K., MacIntyre, D. J., Milburn, K., Navrady, L… Thomson, P. A. (2019). Translational Psychiatry. 

Stress is associated with poorer physical and mental health. This study looked in Generation Scotland and the UK Biobank for evidence of a joint effect of genetic factors for depressive symptoms and stressful life events. Six genes were associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU). Two genetic variants in Generation Scotland showed a gene-by-environment (stress) effect. Polygenic risk score analyses incorporating gene-by-environment effects improved the prediction of depressive symptom scores. This study also provided some evidence of shared origins between depressive symptoms and schizotypal personality, heart disease and chronic obstructive pulmonary disease. 

 

DOLORisk: study protocol for a multi-centre observational study to understand the risk factors and determinants of neuropathic pain. Pascal, M. M. V., Themistocleous, A. C., Baron, R., Binder, A., Bouhassira, D., Crombez, G… Bennett DLH. (2019). Wellcome Open Research.

Neuropathic pain is common in older people and has a major impact on health and quality of life. However, why some but not others develop and suffer chronically from pain is poorly understood. Clinical, genetic and psychosocial factors all contribute, but until now these have not been studied in large cohorts. Generation Scotland is one of several cohorts that have been brought together by the DOLORisk study to study these factors. This paper describes how the study will be conducted and what measures will be made.

 

The Neurobiology of Personal Control During Reward Learning and Its Relationship to Mood. Romaniuk, L., Sandu, A. L., Waiter, G. D., McNeil, C, J., Xueyi, S., Harris, M. A… Whalley, H. C. (2019). Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

 As part of the STRADL project, Generation Scotland participants were invited to take part in a brain imaging study. Here, the aim was to see how individuals respond are motivated and respond to reward tasks. These are known to be affected by personality and depression. This early-stage study confirms and extends previous studies and will be returned to when the full STRADL dataset is available. 

 

Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP. Wigmore, E. M., Hafferty, J. D., Hall, L. S., Howard, D. M., Clarke, T. K., Fabbri, C… McIntosh, A. M. (2019). Pharmacogenomics.

All too often, patients with major depressive disorder do not respond well to the first prescribed antidepressants. This study used prescription data from Generation Scotland to look at antidepressant treatment resistance, as inferred by switching from one treatment to another. No significant genetic effects were found, but correlations between antidepressant treatment resistance and neuroticism, psychological distress, schizotypy and mood disorder traits were identified. Larger sample sizes and better genetic data hold promise for future studies aimed at improving first choice of antidepressant for effective treatment (personalised and precision medicine). 

 

Multi-ancestry genome-wide association study incorporating gene-alcohol interactions identifies new lipid loci. de Vries, P. S., Brown, M. R., Bentley, A. R., Sung, Y. J., Winkler, T. W., Ntalla, I… Morrison, A. C. (2019). American Journal of Epidemiology.

Generation Scotland was one of several cohorts (nearly 400,000 participants from 5 ethnic backgrounds) that were combined to test whether an individual's lipid profile (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides) was influenced by genetic variants and alcohol consumption. 147 independent genetic loci (18 novel) were significantly associated with lipid levels, but none for genes-by-alcohol alone. 

 

Multi-Ancestry Study of Blood Lipid Levels Identifies Four Loci Interacting with Physical Activity. Kilpeläinen, T. O., Bentley, A.R., Noordam, R., Sung, Y. J., Schwander, K., Winkler, T. W… Loos, R. J. F. (2019). Nature Communications.

This multi-cohort, multi-ethnic study (~120,000 individuals of European, African, Asian, Hispanic, and Brazilian ancestry) looked at how physical activity and genetics combine to affect the levels of circulating lipids (HDL cholesterol, LDL cholesterol, and triglyceride levels). Four gene loci, in or near CLASP1, LHX1, SNTA1 and CNTNAP2 were found. 

 

A validation of the diathesis-stress model for depression in Generation Scotland. Arnau-Soler, A., Adams, M. J., Clark, T-K., Macintyre, D. J., Milburn, K., Navrady, L… Thomson, P. A. (2019). Translational Psychaitry.

The diathesis-stress theory to explain depression assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. This theory was tested of a sample of ~5,000 Generation Scotland participants. The study found that those with a high burden of genetic risk reported higher levels of stressful life events. Interestingly, men with a high genetic risk but no recent stressful life events (SLEs) were still at increase risk of depression, whereas in women the absence of recent stressful life events seemed to be protective against depression.  Larger sample sizes are needed to validate these findings.

 

Genetic and Environmental Determinants of Stressful Life Events and their Overlap with Depression and NeuroticismClarke, T-K., Zeng, Y., Navrady, L., Xia, C., Haley, C., Campbell, A… McIntosh, A. M. (2019). Wellcome Open Research.

This study investigates the genetic and environmental contributions to stressful life events in nearly 10,000 Generation Scotland participants with genetic data and information on depression, neuroticism and recent stressful life events.  Recent (past 6-month) stressful life events were positively associated with lifetime depression and neuroticism.  There was a significant effect of couple shared environment.  These findings suggest that stressful life events should not be regarded solely as environmental risk factors for depression as they are partially heritable and this heritability is shared with risk for depression and neuroticism. 

 

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.  Erzurumluoglu, M. A., Liu, M., Jackson, V. E., Barnes, D. R., Gargi, D., Melbourne, C. A… Howson, M. (2019). Molecular Psychiatry.

We collected information on cigarette smoking behaviour in Generation Scotland which was combined with several other cohorts to test for genetic effects on starting/stopping, length of time and number of cigarettes smoked. Several new genetic findings were made that might help identify potential drug targets for smoking prevention and/or cessation.