Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

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Analysis of shared heritability in common disorders of the brain

Effects of physical exercise on anxiety, depression, and sensitivity to stress: a unifying theory.

Introduction: Age-associated cognitive decline—or normal (non-pathological, normative, usual) cognitive ageing—is an important human experience which differs in extent between individuals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences. Areas of agreement and controversy: The phenotype of normal cognitive ageing is well described. Some mental capabilities are well maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory and executive functions, some of which is underpinned by a decline in a general cognitive factor. There are contributions to understanding individual differences in normal cognitive ageing from genetics, general health and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet and lifestyle. Many of these effect sizes are small; some are poorly replicated; and in some cases, there is the possibility of reverse causation, with prior cognitive ability causing the supposed ‘cause’ of cognitive ability in old age. Emerging areas for developing research: Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive ageing is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation and lifestyle factors such as exercise. There are marked advances in brain imaging, affording better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily ageing also influence cognitive functions in old age.

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Age-associated cognitive decline

We review new findings and new theoretical developments in the field of intelligence New findings include the following: (a) Heritability of IQ varies significantly by social class (b) Almost no genetic polymorphisms have been discovered that are consistently associated with variation in IQ in the normal range (c) Much has been learned about the biological underpinnings of intelligence (d) "Crystallized" and "fluid" IQ are quite different aspects of intelligence at both the behavioral and biological levels (e) The importance of the environment for IQ is established by the 12-point to 18-point increase in IQ when children are adopted from working-class to middle-class homes (f) Even when improvements in IQ produced by the most effective early childhood interventions fail to persist, there can be very marked effects on academic achievement and life outcomes (g) In most developed countries studied, gains on IQ tests have continued, and they are beginning in the developing world (h) Sex differences in aspects of intelligence are due partly to identifiable biological factors and partly to socialization factors (i) The IQ gap between Blacks and Whites has been reduced by 033 SD in recent years We report theorizing concerning (a) the relationship between working memory and intelligence, (b) the apparent contradiction between strong heritability effects on IQ and strong secular effects on IQ, (c) whether a general intelligence factor could arise from initially largely independent cognitive skills, (d) the relation between self-regulation and cognitive skills, and (e) the effects of stress on intelligence

Intelligence: New findings and theoretical developments.

Brain Derived Neurotrophic Factor (BDNF) is a key molecule involved in plastic changes related to learning and memory. The expression of BDNF is highly regulated, and can lead to great variability in BDNF levels in healthy subjects. Changes in BDNF expression are associated with both normal and pathological aging and also psychiatric disease, in particular in structures important for memory processes such as the hippocampus and parahippocampal areas. Some interventions like exercise or antidepressant administration enhance the expression of BDNF in normal and pathological conditions. In this review, we will describe studies from rodents and humans to bring together research on how BDNF expression is regulated, how this expression changes in the pathological brain and also exciting work on how interventions known to enhance this neurotrophin could have clinical relevance. We propose that, although BDNF may not be a valid biomarker for neurodegenerative/neuropsychiatric diseases because of its disregulation common to many pathological conditions, it could be thought of as a marker that specifically relates to the occurrence and/or progression of the mnemonic symptoms that are common to many pathological conditions.

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Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain.

Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite life's ‘slings and arrows of outrageous fortune’, do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype–environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

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The heritability of general cognitive ability increases linearly from childhood to young adulthood

Ambulatory assessment of parasympathetic/sympathetic balance by impedance cardiography

Aerobic fitness and the physiological stress response: a critical evaluation.

Effects of aerobic fitness training on heart rate variability and cardiac baroreflex sensitivity

This article reviews the evidence that regular aerobic exercise counters the detrimental effects of psychological stress and prevents stress-related disease. We conclude that the commonly held belief in the stress-alleviating effects of exercise seems to derive mostly from its acute and short-lasting mood effects. Lasting changes in psychological well-being have been found after an aerobic training program, but only in (clinically) anxious or depressed subjects. There is currently no evidence for an attenuating effect of aerobic fitness training on psychophysiological reactivity to stress. However, no study has taken the genetic make-up of individual persons into account, so that selective beneficial effects of exercise in genetically sensitive persons may have gone undetected.

In contrast to the absence of psychological or psychophysiological effects of aerobic exercise, clear beneficial effects of training have been shown on all disease risk factors (e.g. heart rate, blood pressure, haemostasis, cholesterol). These health benefits suffice to strongly encourage the promotion of aerobic fitness programs to compensate for the aversive effects of daily stress.

E.J.C. de Geus

Papers

The heritability of general cognitive ability increases linearly from childhood to young adulthood

Ambulatory assessment of parasympathetic/sympathetic balance by impedance cardiography

Aerobic fitness and the physiological stress response: a critical evaluation.

Effects of aerobic fitness training on heart rate variability and cardiac baroreflex sensitivity

Aerobic Exercise and Stress Reduction