Genetic story jumps ahead

Does the Edinburgh Deary gang never sleep? Just when you expect them to put down their pneumatic drills and have a cup of tea, they come up with two very interesting papers which link the genome to intelligence, personality and health.

We need a name for these sorts of findings: Pleotropic Pandora-ism? The System Integrity Nexus? The Infinite and Ubiquitous Network of Causes? (OK, I stole the last one from Borges, “la infinita/Y ubicua red de causas”  but why not? It was taken from “Elvira de Alvear” a beautiful poem written about a generous and courteous lady who suffered a long mental collapse, so it is close to this team’s work on mind and health and ageing).

Anyway, what have these industrious Scots been up to?

Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N = 112 151) and 24 GWAS consortia.

http://biorxiv.org/content/early/2015/11/10/031120

They say: The causes of the known associations between poorer cognitive function and many adverse neuropsychiatric outcomes, poorer physical health, and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric, and cognitive traits in the participants of UK Biobank, a very large population-based sample (N = 112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics applied to the method of linkage disequilibrium regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, BMI, intracranial volume, infant head circumference, and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.

Well, in decades gone by, few would have predicted that. Intelligence was something which applied to school work (if it applied to anything at all) and perhaps to the evaluation of brain-damaged patients and child development, but it had nothing to do with serious matters like physical and severe mental health disorders. Even though the general drift of modern genetic research has been going in this direction, the results are still astounding.

Three cognitive tests were used. The Reaction Time test was a computerized ‘Snap’ game, in which participants were to press a button as quickly as possible when two ‘cards’ on screen were matching. There were eight experimental trials, with a Cronbach α reliability of 0.85. In the Memory test, participants were shown a set of twelve cards (six pairs) on a computer screen for five seconds, and had to recall which were matching after the cards had been obscured. We used the number of errors in this task as the (inverse) measure of Memory ability. The Verbal-numerical Reasoning task involved a series of thirteen items assessing verbal and arithmetical deduction (Cronbach α reliability = 0.62).

Linkage Disequilibrium score regression was used to derive genetic correlations to determine the degree to which the polygenic architecture of a trait overlaps with that of another. Next, the polygenic risk score method was used to test the extent to which these genetic correlations are predictive of phenotypic variance across samples. Both LD score regression and polygenic risk scores are dependent on the traits analysed being highly polygenic in nature, i.e. where a large number of variants of small effect contribute toward phenotypic variation.

Here is a table which one day will find its way into psychology textbooks. The correlations above the diagonal shouldn’t really exist, and yet there they are. They show a link between the chemical code of life and the skills of life itself.

In Table 2 they show links between the cognitive measures and: coronary heart disease, ischaemic stroke, Alzheimer’s Disease; Autism, Bipolar disease; Major depressive disorder, Schizophrenia, Intercranial volume, Infant Head Circumference, BMI, height, childhood cognitive ability, college education and years of education. The last three load on verbal-numerical ability, but not memory or reaction time. Perhaps all this is better depicted on a heat map:

 

The picture is becoming clearer. There is a link between cognitive ability and health because the causal code of life for a good body and a good mind operates on shared pathways.

How about personality?

Pleiotropy between neuroticism and physical and mental health: findings from 108,038 men and women in UK Biobank.

http://biorxiv.org/content/early/2015/11/10/031138

There is considerable evidence that people with higher levels of the personality trait of neuroticism have an increased risk of several types of mental disorder. Higher neuroticism has also been associated, less consistently, with increased risk of various physical health outcomes. We hypothesised that these associations may, in part, be due to shared genetic influences. We tested for pleiotropy between neuroticism and 12 mental and physical diseases or health traits using linkage disequilibrium regression and polygenic profile scoring. Genetic correlations were derived between neuroticism scores in 108,038 people in UK Biobank and health-related measures from 12 large genome-wide association studies(GWAS). Summary information for the 12 GWAS was used to create polygenic risk scores for the health-related measures in the UK Biobank participants. Associations between the health-related polygenic scores and neuroticism were examined using regression, adjusting for age, sex, genotyping batch, genotyping array, assessment centre, and population stratification. Genetic correlations were identified between neuroticism and anorexia nervosa(rg = 0.17), major depressive disorder (rg = 0.66) and schizophrenia (rg = 0.21). Polygenic risk for several health-related measures were associated with neuroticism, in a positive direction in the case of bipolar disorder (β = 0.017), major depressive disorder (β = 0.036), schizophrenia (β = 0.036), and coronary artery disease (β = 0.011), and in a negative direction in the case of BMI (β = -0.0095). These findings indicate that a high level of pleiotropy exists between neuroticism and some measures of mental and physical health, particularly major depressive disorder and schizophrenia.

Participants completed the Neuroticism scale of the Eysenck Personality QuestionnaireRevised Short Form (EPQ-R Short Form). This scale has been concurrently validated in older people against two of the most widely-used measures of neuroticism, taken from the International Personality Item Pool (IPIP) and the NEO-Five Factor Inventory (NEO-FFI); it correlated -0.84 with the IPIP-Emotional Stability scale and 0.85 with the NEO-FFI Neuroticism scale. A previous study found a high genetic correlation (0.91) between the EPQ-R Short Form Neuroticism scale and psychological distress assessed in a nonpsychiatric population using the 30-item General Health Questionnaire.

Neuroticism is not a good trait to have (say I with a worried expression on my face). People who are higher in neuroticism have an increased risk of developing common mental disorders such as mood, anxiety, somatoform and substance use disorders, and also schizophrenia, bipolar disorder and attention deficit hyperactivity disorder. Higher neuroticism is associated with personality disorders, major depression, generalised anxiety, panic disorders and phobias, and alcohol and drug dependence, antisocial personality and conduct disorders. It is even linked with risk of developing Alzheimer’s disease. Perhaps, if you are of similarly “vigilant” disposition, I should have warned you to skip the above paragraph, but I knew that your eyes would be anxiously drawn to this gloomy list anyway, so why waste time in pointless reassurance? We are doomed, utterly doomed.

Here is a picture of the results:

In very quick summary, three domains of enquiry: cognitive ability, personality and health, have been brought together and shown to rely on common genetic pathways, a causal overlap of significant proportions. These two papers follow a steady drumbeat of high quality research, showing genetic associations with a broad range of important human behaviours. However, although they are in that tradition, they also reveal a considerable speeding up of the discovery rate, and in the power of the findings. These results will cause excitement in informed circles (and has already done so among the first readers) and have a very good chance of being seen as landmark papers.