Multi-organ imaging-derived polygenic indexes for brain and body health.

The UK Biobank (UKB) imaging project is a crucial resource for biomedical research, but is limited to 100,000 participants due to cost and accessibility barriers. Here we used genetic data to predict heritable imaging-derived phenotypes (IDPs) for a larger cohort. We developed and evaluated 4,375 IDP genetic scores (IGS) derived from UKB brain and body images. When applied to UKB participants who were not imaged, IGS revealed links to numerous phenotypes and stratified participants at increased risk for both brain and somatic diseases. For example, IGS identified individuals at higher risk for Alzheimer's disease and multiple sclerosis, offering additional insights beyond traditional polygenic risk scores of these diseases. When applied to independent external cohorts, IGS also stratified those at high disease risk in the All of Us Research Program and the Alzheimer's Disease Neuroimaging Initiative study. Our results demonstrate that, while the UKB imaging cohort is largely healthy and may not be the most enriched for disease risk management, it holds immense potential for stratifying the risk of various brain and body diseases in broader external genetic cohorts.

Science for policy to protect children in cyberspace.

Cross-disciplinary partnerships are needed to formulate policies that account for developmental vulnerabilities.

Neuroanatomical correlates of genetic risk for obesity in children.

Obesity has a strong genetic component, with up to 20% of variance in body mass index (BMI) being accounted for by common polygenic variation. Most genetic polymorphisms associated with BMI are related to genes expressed in the central nervous system. At the same time, higher BMI is associated with neurocognitive changes. However, the direct link between genetics of obesity and neurobehavioral mechanisms related to weight gain is missing. Here, we use a large sample of participants (n > 4000) from the Adolescent Brain Cognitive Development cohort to investigate how genetic risk for obesity, expressed as polygenic risk score for BMI (BMI-PRS), is related to brain and behavioral measures in adolescents. In a series of analyses, we show that BMI-PRS is related to lower cortical volume and thickness in the frontal and temporal areas, relative to age-expected values. Relatedly, using structural equation modeling, we find that lower overall cortical volume is associated with higher impulsivity, which in turn is related to an increase in BMI 1 year later. In sum, our study shows that obesity might partially stem from genetic risk as expressed in brain changes in the frontal and temporal brain areas, and changes in impulsivity.

Pattern learning reveals brain asymmetry to be linked to socioeconomic status.

Socioeconomic status (SES) anchors individuals in their social network layers. Our embedding in the societal fabric resonates with habitus, world view, opportunity, and health disparity. It remains obscure how distinct facets of SES are reflected in the architecture of the central nervous system. Here, we capitalized on multivariate multi-output learning algorithms to explore possible imprints of SES in gray and white matter structure in the wider population (n ≈ 10,000 UK Biobank participants). Individuals with higher SES, compared with those with lower SES, showed a pattern of increased region volumes in the left brain and decreased region volumes in the right brain. The analogous lateralization pattern emerged for the fiber structure of anatomical white matter tracts. Our multimodal findings suggest hemispheric asymmetry as an SES-related brain signature, which was consistent across six different indicators of SES: degree, education, income, job, neighborhood and vehicle count. Hence, hemispheric specialization may have evolved in human primates in a way that reveals crucial links to SES.

Human brain anatomy reflects separable genetic and environmental components of socioeconomic status.

Socioeconomic status (SES) correlates with brain structure, a relation of interest given the long-observed relations of SES to cognitive abilities and health. Yet, major questions remain open, in particular, the pattern of causality that underlies this relation. In an unprecedently large study, here, we assess genetic and environmental contributions to SES differences in neuroanatomy. We first establish robust SES-gray matter relations across a number of brain regions, cortical and subcortical. These regional correlates are parsed into predominantly genetic factors and those potentially due to the environment. We show that genetic effects are stronger in some areas (prefrontal cortex, insula) than others. In areas showing less genetic effect (cerebellum, lateral temporal), environmental factors are likely to be influential. Our results imply a complex interplay of genetic and environmental factors that influence the SES-brain relation and may eventually provide insights relevant to policy.

Associations between alcohol consumption and gray and white matter volumes in the UK Biobank.

Heavy alcohol consumption has been associated with brain atrophy, neuronal loss, and poorer white matter fiber integrity. However, there is conflicting evidence on whether light-to-moderate alcohol consumption shows similar negative associations with brain structure. To address this, we examine the associations between alcohol intake and brain structure using multimodal imaging data from 36,678 generally healthy middle-aged and older adults from the UK Biobank, controlling for numerous potential confounds. Consistent with prior literature, we find negative associations between alcohol intake and brain macrostructure and microstructure. Specifically, alcohol intake is negatively associated with global brain volume measures, regional gray matter volumes, and white matter microstructure. Here, we show that the negative associations between alcohol intake and brain macrostructure and microstructure are already apparent in individuals consuming an average of only one to two daily alcohol units, and become stronger as alcohol intake increases.

Determining the effects of training duration on the behavioral expression of habitual control in humans: a multilaboratory investigation.

It has been suggested that there are two distinct and parallel mechanisms for controlling instrumental behavior in mammals: goal-directed actions and habits. To gain an understanding of how these two systems interact to control behavior, it is essential to characterize the mechanisms by which the balance between these systems is influenced by experience. Studies in rodents have shown that the amount of training governs the relative expression of these two systems: Behavior is goal-directed following moderate training, but the more extensively an instrumental action is trained, the more it becomes habitual. It is less clear whether humans exhibit similar training effects on the expression of goal-directed and habitual behavior, as human studies have reported contradictory findings. To tackle these contradictory findings, we formed a consortium, where four laboratories undertook a preregistered experimental induction of habits by manipulating the amount of training. There was no statistical evidence for a main effect of the amount of training on the formation and expression of habits. However, exploratory analyses suggest a moderating effect of the affective component of stress on the impact of training over habit expression. Participants who were lower in affective stress appeared to be initially goal-directed, but became habitual with increased training, whereas participants who were high in affective stress were already habitual even after moderate training, thereby manifesting insensitivity to overtraining effects. Our findings highlight the importance of the role of moderating variables such as individual differences in stress and anxiety when studying the experimental induction of habits in humans.

Impact of ambient sound on risk perception in humans: neuroeconomic investigations.

Research in the field of multisensory perception shows that what we hear can influence what we see in a wide range of perceptual tasks. It is however unknown whether this extends to the visual perception of risk, despite the importance of the question in many applied domains where properly assessing risk is crucial, starting with financial trading. To fill this knowledge gap, we ran interviews with professional traders and conducted three laboratory studies using judgments of financial asset risk as a testbed. We provide evidence that the presence of ambient sound impacts risk perception, possibly due to the combination of facilitatory and synesthetic effects of general relevance to the perception of risk in many species as well as humans. We discuss the implications of our findings for various applied domains (e.g., financial, medical, and military decision-making), and raise new questions for future research.

Genetic underpinnings of risky behaviour relate to altered neuroanatomy.

Previous research points to the heritability of risk-taking behaviour. However, evidence on how genetic dispositions are translated into risky behaviour is scarce. Here, we report a genetically informed neuroimaging study of real-world risky behaviour across the domains of drinking, smoking, driving and sexual behaviour in a European sample from the UK Biobank (N = 12,675). We find negative associations between risky behaviour and grey-matter volume in distinct brain regions, including amygdala, ventral striatum, hypothalamus and dorsolateral prefrontal cortex (dlPFC). These effects are replicated in an independent sample recruited from the same population (N = 13,004). Polygenic risk scores for risky behaviour, derived from a genome-wide association study in an independent sample (N = 297,025), are inversely associated with grey-matter volume in dlPFC, putamen and hypothalamus. This relation mediates roughly 2.2% of the association between genes and behaviour. Our results highlight distinct heritable neuroanatomical features as manifestations of the genetic propensity for risk taking.

No evidence for a difference in 2D:4D ratio between youth with elevated prenatal androgen exposure due to congenital adrenal hyperplasia and controls.

The second-to-fourth digit ratio (2D:4D) has been associated with sexual dimorphism, with a lower 2D:4D in males. A large body of research has relied on the 2D:4D as a proxy for prenatal androgen exposure, and includes reports of relationships between 2D:4D and a wide range of human traits. Here, we examine the validity of the 2D:4D proxy by studying the association between 2D:4D and classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a condition characterized by excessive prenatal exposure to androgens during most of the gestational period. To this end, we retrospectively examine 513 serial radiographs of the left hand obtained clinically in 90 youth with classical CAH (45 female) and 70 control youth (31 female). Replicating previous reports, we observe associations of the 2D:4D with sex (lower 2D:4D in males) and age (increase of 2D:4D through development). However, we find no evidence for differences in 2D:4D between CAH and controls (full sample: ß = -0.001 (-0.008, 0.006); females: ß = -0.004 [-0.015, 0.007]; males: ß = 0.001, [-0.008, 0.011]). Although our findings do not rule out a small association between the 2D:4D and CAH, they cast doubt on the usefulness of the 2D:4D as a biomarker for prenatal androgen exposure in behavioral research.

Do sex hormones at birth predict later-life economic preferences? Evidence from a pregnancy birth cohort study.

Economic preferences may be shaped by exposure to sex hormones around birth. Prior studies of economic preferences and numerous other phenotypic characteristics use digit ratios (2D : 4D), a purported proxy for prenatal testosterone exposure, whose validity has recently been questioned. We use direct measures of neonatal sex hormones (testosterone and oestrogen), measured from umbilical cord blood (n = 200) to investigate their association with later-life economic preferences (risk preferences, competitiveness, time preferences and social preferences) in an Australian cohort (Raine Study Gen2). We find no significant associations between testosterone at birth and preferences, except for competitiveness, where the effect runs opposite to the expected direction. Point estimates are between 0.05-0.09 percentage points (pp) and 0.003-0.14 s.d. We similarly find no significant associations between 2D : 4D and preferences (n = 533, point estimates 0.003-0.02 pp and 0.001-0.06 s.d.). Our sample size allows detecting effects larger than 0.11 pp or 0.22 s.d. for testosterone at birth, and 0.07 pp or 0.14 s.d. for 2D : 4D (α = 0.05 and power = 0.90). Equivalence tests show that most effects are unlikely to be larger than these bounds. Our results suggest a reinterpretation of prior findings relating 2D : 4D to economic preferences, and highlight the importance of future large-sample studies that permit detection of small effects.

The default network of the human brain is associated with perceived social isolation.

Humans survive and thrive through social exchange. Yet, social dependency also comes at a cost. Perceived social isolation, or loneliness, affects physical and mental health, cognitive performance, overall life expectancy, and increases vulnerability to Alzheimer's disease-related dementias. Despite severe consequences on behavior and health, the neural basis of loneliness remains elusive. Using the UK Biobank population imaging-genetics cohort (n = ~40,000, aged 40-69 years when recruited, mean age = 54.9), we test for signatures of loneliness in grey matter morphology, intrinsic functional coupling, and fiber tract microstructure. The loneliness-linked neurobiological profiles converge on a collection of brain regions known as the 'default network'. This higher associative network shows more consistent loneliness associations in grey matter volume than other cortical brain networks. Lonely individuals display stronger functional communication in the default network, and greater microstructural integrity of its fornix pathway. The findings fit with the possibility that the up-regulation of these neural circuits supports mentalizing, reminiscence and imagination to fill the social void.

Digit ratio (2D:4D) and congenital adrenal hyperplasia (CAH): Systematic literature review and meta-analysis.

The ratio of length between the second and fourth fingers (2D:4D) is commonly used as an indicator of prenatal sex hormone exposure. Several approaches have been used to try to validate the measure, including examining 2D:4D in people with congenital adrenal hyperplasia (CAH), a suite of conditions characterised by elevated adrenal androgen production secondary to defective steroidogenesis. We present a systematic review and meta-analysis that examines the relationship between these two variables. Twelve articles relating to nine CAH cohorts were identified, and 2D:4D comparisons have been made between cases and controls in eight of these cohorts. Altogether, at least one 2D:4D variable has been compared between n = 251 females with CAH and n = 358 unaffected females, and between n = 108 males with CAH and n = 204 unaffected males. A previous meta-analysis (Hönekopp and Watson, 2010) reported lower right hand (R2D:4D) and left hand (L2D:4D) digit ratios in patients with CAH relative to sex-matched controls. Our meta-analysis showed the same pattern, with medium effect sizes for R2D:4D and small effect sizes for L2D:4D. Differences of small magnitude were also observed for M2D:4D, and no significant effects were observed for D[R-L]. Notably, the only effects that remained statistically significant when stratified by sex were R2D:4D in males and L2D:4D in females, and the average effect size had reduced by 46.70% since the meta-analysis of Hönekopp and Watson (2010). We also found that individual comparisons in this literature were considerably underpowered, and that patterns of sexual dimorphism in 2D:4D were similar in CAH samples as in typically developing populations. Findings are discussed in relation to the prenatal androgen hypothesis as well as alternative explanations.

Autonomy in consumer choice.

We propose that autonomy is a crucial aspect of consumer choice. We offer a definition that situates autonomy among related constructs in philosophy and psychology, contrast actual with perceived autonomy in consumer contexts, examine the resilience of perceived autonomy, and sketch out an agenda for research into the role of perceived autonomy in an evolving marketplace increasingly characterized by automation.

Predicting the replicability of social science lab experiments.

We measure how accurately replication of experimental results can be predicted by black-box statistical models. With data from four large-scale replication projects in experimental psychology and economics, and techniques from machine learning, we train predictive models and study which variables drive predictable replication. The models predicts binary replication with a cross-validated accuracy rate of 70% (AUC of 0.77) and estimates of relative effect sizes with a Spearman ρ of 0.38. The accuracy level is similar to market-aggregated beliefs of peer scientists [1, 2]. The predictive power is validated in a pre-registered out of sample test of the outcome of [3], where 71% (AUC of 0.73) of replications are predicted correctly and effect size correlations amount to ρ = 0.25. Basic features such as the sample and effect sizes in original papers, and whether reported effects are single-variable main effects or two-variable interactions, are predictive of successful replication. The models presented in this paper are simple tools to produce cheap, prognostic replicability metrics. These models could be useful in institutionalizing the process of evaluation of new findings and guiding resources to those direct replications that are likely to be most informative.

Does testosterone impair men's cognitive empathy? Evidence from two large-scale randomized controlled trials.

The capacity to infer others' mental states (known as 'mind reading' and 'cognitive empathy') is essential for social interactions across species, and its impairment characterizes psychopathological conditions such as autism spectrum disorder and schizophrenia. Previous studies reported that testosterone administration impaired cognitive empathy in healthy humans, and that a putative biomarker of prenatal testosterone exposure (finger digit ratios) moderated the effect. However, empirical support for the relationship has relied on small sample studies with mixed evidence. We investigate the reliability and generalizability of the relationship in two large-scale double-blind placebo-controlled experiments in young men (n = 243 and n = 400), using two different testosterone administration protocols. We find no evidence that cognitive empathy is impaired by testosterone administration or associated with digit ratios. With an unprecedented combined sample size, these results counter current theories and previous high-profile reports, and demonstrate that previous investigations of this topic have been statistically underpowered.

Are Bigger Brains Smarter? Evidence From a Large-Scale Preregistered Study.

A positive relationship between brain volume and intelligence has been suspected since the 19th century, and empirical studies seem to support this hypothesis. However, this claim is controversial because of concerns about publication bias and the lack of systematic control for critical confounding factors (e.g., height, population structure). We conducted a preregistered study of the relationship between brain volume and cognitive performance using a new sample of adults from the United Kingdom that is about 70% larger than the combined samples of all previous investigations on this subject ( N = 13,608). Our analyses systematically controlled for sex, age, height, socioeconomic status, and population structure, and our analyses were free of publication bias. We found a robust association between total brain volume and fluid intelligence ( r = .19), which is consistent with previous findings in the literature after controlling for measurement quality of intelligence in our data. We also found a positive relationship between total brain volume and educational attainment ( r = .12). These relationships were mainly driven by gray matter (rather than white matter or fluid volume), and effect sizes were similar for both sexes and across age groups.

Testing the influence of testosterone administration on men's honesty in a large laboratory experiment.

The impact of testosterone on decision-making is a growing literature, with several reports of economically relevant outcomes. Similar to Wibral et al. (2012), we investigate the effects of exogenous testosterone administration on deception in a double-blind placebo controlled study. Participants (N = 242) were asked to roll a die in private and were paid according to their reported roll, which creates the opportunity to lie about the outcome to increase earnings. We find evidence for self-serving lying in both treatment and control groups and a statistically insignificant negative effect (d = -0.17, 95% CI[-0.42, 0.08]) indicating more honest behavior (i.e., lower reports) following testosterone administration. Although insignificant, the direction was the same as in the Wibral et al. study, and the meta-analytic effect of the two studies demonstrates lower reporting (i.e., more honesty) following testosterone (vs. placebo) administration, significant at the 0.05 level (d = -0.27, 95% CI[-0.49, -0.06]). We discuss how our results and methodology compare with Wibral et al. and identify potential causes for differences in findings. Finally, we consider several plausible connections between testosterone and lying that may be further investigated using alternative methodologies.