Generation Scotland

2015

Research publications from 2015

Polygenic risk of ischemic stroke is associated with cognitive ability. Harris, S. E., Malik, R., Marioni, R., Campbell, A., Seshadri, S., Worrall, B. B., … Deary, I. J. (2015). Neurology, 86(7), 611–618.

This study shows that polygenic risk scores for stroke are also associated with lower cognitive ability (thinking skills). This is true even in the absence of stroke, consistent with a common risk pathway.

 

Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Johnson, M. R., Shkura, K., Langley, S. R., Delahaye-Duriez, A., Srivastava, P., Hill, W. D., … Petretto, E. (2015). Nature Neuroscience, 19(2), 223-232.

There is strong evidence for genetic influence in the way our brains develop and, in turn, the individual differences in our thinking skills. In this important study, Generation Scotland was one of several cohorts that combined data to show that genes identified in studies of abnormal brain development affect the same biologial processes as those that account for individual differences in thinking skills.

 

Timing, rates and spectra of human germline mutation. Rahbari, R., Wuster, A., Lindsay, S. J., Hardwick, R. J., Alexandrov, L. B., Al Turki, S., … Hurles, M. E. (2015). Nature Genetics, 48(2), 126-133.

The family based structure of Generation Scotland allows us to look at how genetic information is passed down from one generation to the next and, as in this large collaborative study,  how often and when mutations arise. This study provides new guidance to clinical geneticists when assessing the likey recurrence of inherited diseases in families.

 

Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation. Soler Artigas, M., Wain, L. V., Miller, S., Kheirallah, A. K., Huffman, J. E., Ntalla, I., … Tobin, M. D. (2015). Nature Communications, 6, 8658.

This study builds upon earlier collaborative work with Generation Scotland, using advanced statistical methods to increase the sensitivity of the original genetic analyses and thus identifying 16 new genetic loci that infuence lung function.

 

Epidemiology and Heritability of Major Depressive Disorder, Stratified by Age of Onset, Sex, and Illness Course in Generation Scotland: Scottish Family Health Study (GS:SFHS). Fernandez-Pujals, A. M., Adams, M. J., Thomson, P., McKechanie, A. G., Blackwood, D. H. R., Smith, B. H., … McIntosh, A. M. (2015). PLoS ONE, 10(11), e0142197.

Great effort was made to collect deep and high quality information from Generation Scotland participants on both physical and mental health at the time of recruitment (2006-2011). Genetic data was added later. This study looks at genetic factors that are associated with depression and reports significant group differences according to age of onset, whether male or female and whether participants had a single episode or recurrent episodes of depression.

 

Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C. van Leeuwen, E. M., Huffman, J. E., Bis, J. C., Isaacs, A., Mulder, M., Sabo, A., … van Duijn, C. (2015). npj Aging and Mechanisms of Disease.

A genetic variant in the gene CETP is well known to associate with higher levels of the HDL-C. Generation Scotland contributed data to this study which sought to find additional genetic evidence to explain this association. Five variants in the CETP gene were identified that may help explain the association between CETP and HDL-C and account for the added association with longevity.

 

Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.  Timofeeva, M. N., Kinnersley, B., Farrington, S. M., Whiffin, N., Palles, C., Svinti, V., … Houlston, R. S. (2015). Scientific Reports, 5, 16286.

Genetic studies have established unequivocal links to specific mutations in a range of cancers including colorectal cancer, but some genetic effects remain hidden. This study, using Generation Scotland data as a control sample, looked for evidence on recurring rare mutations in colon cancer and concluded that this did not account for the missing heritablity (genetic contribution).

 

Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomization Meta-Analysis in the CARTA Consortium. Linneberg, A., Jacobsen, R. K., Skaaby, T., Taylor, A. E., Fluharty, M. E., Jeppesen, J. L., … Husemoen, L. L. (2015). Circulation: Cardiovascular Genetics 8(6), 832-841.

Generation Scotland contributed data to the CARTA consortium and shows that a gene that is associated with heavy smoking is also associated with increased resting heart rate, suggesting this is part of the explanation for why smoking is linked to risk of heart disease.

 

Structural brain MRI trait polygenic score prediction of cognitive abilities. Luciano, M., Marioni, R. E., Hernández, M. V., Maniega, S. M., Hamilton, I. F., Royle, N. A., … Deary, I. J. (2015). Twin Research and Human Genetics : The Official Journal of the International Society for Twin Studies, 18(6), 738–745.

This study looks for links between variation in brain volumes and indicators of brain damage / ageing in relation to mental capacity. We do not yet have brain images for Generation Scotland participants so an indirect measure was used by asking whether genes known from other studies to account for individual differences seen in brain scans predicted cognitive ability in GS. None were seen.

 

Markers of Psychological Differences and Social and Health Inequalities: Possible Genetic and Phenotypic Overlaps. Mottus, R., Marioni, R., Deary, I. J. (2015). Journal of Personality.

The authors draw upon data from Generation Scotland to advance the case for a causal links between intelligence, psychometric and psychiatric traits and general health and social inequalities.

 

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA double strand break repair. Day, F. R., Ruth, K. S., Thompson, D. J., Lunetta, K. L., Pervjakova, N., Chasman, D. I., … Murray, A. (2015). Nature Genetics, 47(11), 1294-1303.

Generation Scotland played a valuable role in this study by providing data from individuals who had been carefully screened to be free from cancer to act as well-matched controls for a study of breast cancer.

 

Differential effects of the APOE e4 allele on different domains of cognitive ability across the life-course. Marioni, R. E., Campbell, A., Scotland, G., Hayward, C., Porteous, D. J., Deary, I. J. (2015). European Journal of Human Genetics.

There is a well described protective role for the e2 and a risk effect of the e4 allele of the APOE gene in dementia. What this study shows is a new facet to that overall relationship: as expected, e4 was associated with lower scores for memory and processing speed across all ages, but in the under 60's it was actually associated with greater verbal fluency.

 

The UK10K project identifies rare variants in health and disease. UK10K Consortium, Walker, K., Min, J. L., Huang, J., Crooks, L., Memari, Y., … Zhang, W. (2015). Nature, 526(7571), 82-90.

The UK10K project was, to date, the largest survey by whole genome sequencing for mutations linked to disease. Over 24 million genetic variants were reported. Several gene mutations that explain clinicially important but otherwise undiagnosed disorders were found. GS contributed a small, but valuable sub-set of samples to this study.

 

Meta-analysis of genome-wide association studies for extraversion: Findings from the Genetics of Personality Consortium. Van den Berg, S. M., de Moor, M. H. M., Verweij, K. J. H., Krueger, R. F., Luciano, M., Vasquez, A. A., … Boomsma, D. I. (2016). Behavior Genetics, 46(2), 170–182.

Extraversion, a quantifiable personality trait that typifies an outgoing, positive nature, is highly heritable, and has been measured in the Generation Scotland Scottish Family Health Study (GS:SFHS). This paper reports on findings fom the combined analysis of 29 cohorts and over 60,000 participants. The main findings were that extraversion is highly polygenic, no genes with individually strong effects were found, and none of the five best candidate loci replicated in GS:SFHS.

 

Sex-Differences in the Metabolic Health of Offspring of Parents with Diabetes: A Record-Linkage Study. Aldhous, M. C., Reynolds, R. M., Campbell, A., Linksted, P., Lindsay, R. S., Smith, B. H., … Generation Scotland. (2015). PLoS ONE, 10(8), e0134883.

This study takes advantage of the capacity to link Generation Scotland participants to routine health records and therefore investigate the consequences of parental diabetes on their children's health.

 

Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium. Morris, R. W., Taylor, A. E., Fluharty, M. E., Bjørngaard, J. H., Åsvold, B. O., Elvestad Gabrielsen, M., … Sattar, N. (2015). BMJ Open, 5(8), e008808.

Generation Scotland contributed data to the  Causal Analysis Research in Tobacco and Alcohol (CARTA) consortium which in this study provides genetic evidence for a direct effect of heavy smoking on waist circumference.

 

Rare coding variants and X-linked loci associated with age at menarche. Lunetta, K. L., Day, F. R., Sulem, P., Ruth, K. S., Tung, J. Y., Hinds, D. A., … Perry, J. R. B. (2015). Nature Communications, 6, 7756.

Age at menarche, the onset of first menstruation in females, indicates the start of reproductive maturity. It is highly heritable. Over 100 genetic variants have been shown to influence this trait, but they only account for a very samll proportion of the heritability. This study looks specifically at the X chromosome (2 copies in females, against a single X plus Y in males) and for evidence that rare protein coding mutations might explain some of the missing heritability. Although the study found some new evidence, the majority of the genetic influence remains hidden.

 

Association between cognition and gene polymorphisms involved in thrombosis and haemostasis. Quinn, T. J., Alghamdi, J., Padmanabhan, S., Porteous, D. J., Smith, B. H., Hocking, L., … Stott, D. J. (2015). Age, 37(4),9820.

Many studies throw up associations between health-related traits, but it is important to distinguish between cause and effect, for example in ageing disorders where memory loss is a natural consequence. Mendelian Randomisation is a powerful test of genetic causation. In this study, genetic polymorphisms for four well-known blood factors were tested in GS for association with cognitive function (thinking skills). No association was found. By contrast, lower scores on cognitive measures were significantly associated with increasing age, socioeconomic deprivation, blood pressure, waist-hip ratio, smoking, and vascular comorbidity.  

 

Homozygous loss-of-function variants in European cosmopolitan and isolate populations. Kaiser, V. B., Svinti, V., Prendergast, J. G., Chau, Y.-Y., Campbell, A., Patarcic, I., … Wilson, J. F. (2015). Human Molecular Genetics, 24(19), 5464–5474.

Identical twins apart, no two individuals in the population are genetically identical. Indeed, we all carry a large number of genetic variants linked to disease. This study looked to find cases where individuals carried damaging mutations on both  parental chromosomes. Several were found. The study points to the fact that some genes are effectively redundant with no major effect on health when both copies are not functioning.

 

Directional dominance on stature and cognition in diverse human populations (ROHgen). Joshi, P. K., Esko, T., Mattsson, H., Eklund, N., Gandin, I., Nutile, T., … Wilson, J. F. (2015). Nature,523(7561), 459-462.

Since Darwin, inbreeding has been associated with reduced fitness. Human populations are generally outbred, the exceptions being in cultures where cousin-cousin marriages are the norm and elevated rates of otherwise rare inherited conditions follow.  This study assessed levels of homozygosity in the genome to test whether these correlated with a range of health related traits.  Longer runs of homozygosity were associeted with lower height, lung function (as measured by FEV1) and thinking skills / educational attainment, but not for 12 other traits that affect heart disease and other late-onset conditions. This study relied upon collating data on over 100,000 individuals from around the world, with GS one such study. The study suggests that increased height, improved lung function and higher intelligence have been positively selected for over human history.

 

Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder. De Moor, M. H. M., van den Berg, S. M., Verweij, K. J. H., Krueger, R. F., Luciano, M., Vasquez, A. A., … Boomsma, D. I. (2015). JAMA Psychiatry, 72(7), 642–650.

Neuroticism is a quantitative personality trait that has been measured in Generation Scotland. This study reports the findings from a meta-analysis of GSplus 29 other cohorts totalling over 63,000 participants. The study reports a new gene locus MAGI1 associated with neuroticism and with major depressive disorder.

 

Major depressive disorder and current psychological distress moderate the effect of polygenic risk for obesity on body mass index. Clarke, T.-K., Hall, L. S., Fernandez-Pujals, A. M., MacIntyre, D. J., Thomson, P., Hayward, C., … McIntosh, A. M. (2015). Translational Psychiatry, 5(6), e592–.

Epidemiological studies have pointed to the fact that depression is more common than expected in obese individuals, and vice-versa, but which is cause and which is effect is unclear. This study uses genetic information to show that individuals who have clinical depression and carry a higher than average burden of genetic risk factors for high body mass index are more likely to develop obesity than individuals without a history of depression.

 

Recent genomic heritage in Scotland. Amador, C., Huffman, J., Trochet, H., Campbell, A., Porteous, D., Generation Scotland, … Haley, C. S. (2015). BMC Genomics, 16(1), 437.

Because Generation Scotland is a population and family based study, it is possible to infer the origins of participants from the genetic information collected. As expected, most are very similar to most continental European populations, but we can also see evidence for sub-groups within Scotland and for individuals whose ancestors have migrated to Scotland, for example from Italy.

 

Current versus lifetime depression, APOE variation, and their interaction on cognitive performance in younger and older adults. Luciano, M., Fernandez-Pujals, A. M., Marioni, R. E., Campbell, A, Hayward, C., MacIntyre, D. J., … Deary, I. J. (2015). Psychosomatic Medicine, 77(5), 480-492.

Loss of mental ability in old age is a common fear. Depression is often seen associated with dementia. The most common genetic factor associated with dementia is APOE4. Generation Scotland data shows that  depression in old age is associated with poorer thinking speed and memory. There was an additional but independent effect of carrying the APOE4 gene.

 

Copy number variation in the human Y chromosome in the UK population. Wei, W., Fitzgerald, T., Ayub, Q., Massaia, A., Smith, B. B., Dominiczak, A. A., … Xue, Y. (2015). Human Genetics, 134(7), 789–800.

The human Y chromosome is specific to males. Relative to the rest of the chromosomes, it has been understudied. This study look to see if like the rest of the genome there were Y chromosome regions that were partially deleted or duplicated in some individuals. Using Generation Scotland data, 22 such regions were identified, 16 of which were novel. Most were rare, but one was remarkably common and therefore likely to be benign. Further work will be needed to test whether any have important biological consequences.

 

GWAS for executive function and processing speed suggests involvement of the CADM2 gene. Ibrahim-Verbaas, C., Bressler, J., Debette, S., Schuur, M., Smith, A., Bis, J., … Mosley, T. (2016). Molecular Psychiatry, 21(2), 189–197.

Generation Scotland was one of several cohorts that combined data to show that a gene variant in the Cell Adhesion Molecule 2 (CADM2) gene was associated with individual differences in information processing speed.

 

Polygenic risk for alcohol dependence associates with alcohol consumption, cognitive function and social deprivation in a population-based cohort. Clarke, T.-K., Smith, A. H., Gelernter, J., Kranzler, H. R., Farrer, L. A., Hall, L. S., ... McIntosh, A. M. (2016). Addiction Biology, 21(2), 469-480.

Generation Scotland collected a lot of information at the time of recruitment about both physical and mental well-being, occupation, lifestyle and habits. This study adds to work from others that points to links between alcohol dependence, social and inherited factors.

 

Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population. Clarke, T.-K., Lupton, M. K., Fernandez-Pujals, A. M., Starr, J., Davies, G., Cox, S., … McIntosh, A. M. (2016). Molecular Psychiatry, 21(3), 419–425.

The core features of autism can present in severe to mild form, hence the modern interpretation of a spectrum disorder, or ASD. We know also of many different genes that can be involved. This study shows that the same genes that contribute to risk of ASD in clinical cases contribute to intellectual capacity in the general population. 

 

Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels. van Leeuwen, E. M., Karssen, L. C., Deelen, J., Isaacs, A., Medina-Gomez, C., Mbarek, H., … van Duijn, C. M. (2015). Nature Communications, 6, 6065.

Blood lipid levels are controlled by many genes and specific mutations have been described that affect these levels. This study sets out a strategy to try to discover more about such variants by carefully comparing mutations found in specific populations, in this case from the Netherlands, in comparison to others. Generation Scotland was one such comparison population. The key finding was that a rare genetic variant in the ABCA6 gene is enriched over 3 fold in the Dutch population and has a clinic effect similar to that of previously reported genetic variants in other well-know lipid genes such as LDLR.

 

Exome sequencing to detect rare variants associated with general cognitive ability: A pilot study. Luciano, M., Svinti, V., Campbell, A., Marioni, R. E., Hayward, C., Wright, A. F., … Deary, I. J. (2015). Twin Research and Human Genetics, 18(2), 117-125.

We have used whole exome sequencing in a modest sub-set of Generation Scotland participants, to start to get an idea as to how much variation there is in the protein coding genes. In this pilot study, we find some evidence to suggest that there are more rare and potentially functional gene variants in individuals who performed best in tests of general cognitive ability. This warrants a larger study.

 

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949). Davies, G., Armstrong, N., Bis, J. C., Bressler, J., Chouraki, V., Giddaluru, S., … Deary, I. J. (2015). Molecular Psychiatry, 20(2), 183–192.

Generation Scotland was one of 31 cohorts that contributed data to CHARGE, a large international research consortium, for this study totalling over 50,000 subjects who had taken tests of learning and memory. Using a general measure of cognitive ability, the study identified 13 genetic variants clustering within 3 regions of the genome  associated with cognitive ability. Although the proportion of individual differences explained was small, the findings were statistically robust. Intriguingly, the gene regions identified overlapped with regions indepently associated with dementia and other mental health disorders.

 

Mosaic structural variation in children with developmental disorders. King, D. A., Jones, W. D., Crow, Y. J., Dominiczak, A. F., Foster, N. A., Gaunt, T. R., … The Deciphering Developmental Disorders Study (2015). Human Molecular Genetics, 24(10), 2733–2745.

Here is another study where Generation Scotland played a valuable role as a reference data set. The study was looking at the frequency of children presenting at a clinic with intellectual disability and assessing how many cases were due to structural changes acquired very soon after conception. Although rare, this form of genetic mosaicism does occur in up to 1% of cases. It is technically difficult to assess. This paper proposes a robust method to do so.

 

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Wessel, J., Chu, A. Y., Willems, S. M., Wang, S., Yaghootkar, H., Brody, J. A., … Goodarzi, M. O. (2015). Nature Communications, 6, 5897.

Insulin and blood glucose levels predict diabetes. This large collaborative study that included Generation Scotland data looked for evidence of rare genetic variants predicted to alter the function of genes associated with these traits. Three novel findings in the GLP1R, G6PC2 and ABO loci were reported.