Elucidating the relationship between migraine risk and brain structure using genetic data.

Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 × 10-3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.

Genetic variants associated with longitudinal changes in brain structure across the lifespan.

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

Shared Genetic Etiology between Cortical Brain Morphology and Tobacco, Alcohol, and Cannabis Use.

Genome-wide association studies (GWAS) have identified genetic variants associated with brain morphology and substance use behaviors (SUB). However, the genetic overlap between brain structure and SUB has not been well characterized. We leveraged GWAS summary data of 71 brain imaging measures and alcohol, tobacco, and cannabis use to investigate their genetic overlap using linkage disequilibrium score regression. We used genomic structural equation modeling to model a "common SUB genetic factor" and investigated its genetic overlap with brain structure. Furthermore, we estimated SUB polygenic risk scores (PRS) and examined whether they predicted brain imaging traits using the Adolescent Behavior and Cognitive Development (ABCD) study. We identified 8 significant negative genetic correlations, including between (1) alcoholic drinks per week and average cortical thickness, and (2) intracranial volume with age of smoking initiation. We observed 5 positive genetic correlations, including those between (1) insula surface area and lifetime cannabis use, and (2) the common SUB genetic factor and pericalcarine surface area. SUB PRS were associated with brain structure variation in ABCD. Our findings highlight a shared genetic etiology between cortical brain morphology and SUB and suggest that genetic variants associated with SUB may be causally related to brain structure differences.

Ten years of enhancing neuro-imaging genetics through meta-analysis: An overview from the ENIGMA Genetics Working Group.

Here we review the motivation for creating the enhancing neuroimaging genetics through meta-analysis (ENIGMA) Consortium and the genetic analyses undertaken by the consortium so far. We discuss the methodological challenges, findings, and future directions of the genetics working group. A major goal of the working group is tackling the reproducibility crisis affecting "candidate gene" and genome-wide association analyses in neuroimaging. To address this, we developed harmonized analytic methods, and support their use in coordinated analyses across sites worldwide, which also makes it possible to understand heterogeneity in results across sites. These efforts have resulted in the identification of hundreds of common genomic loci robustly associated with brain structure. We have found both pleiotropic and specific genetic effects associated with brain structures, as well as genetic correlations with psychiatric and neurological diseases.

The psychosocial impact of nausea and vomiting during pregnancy as a predictor of postpartum depression.

This study examined the extent to which psychosocial impact of nausea and vomiting during pregnancy predicts postpartum depression using a retrospective design. Data from a cross-sectional survey investigating women's experiences of nausea and vomiting during pregnancy were used (N = 861). Hierarchical logistic regression models revealed that the psychosocial impact of nausea and vomiting in pregnancy appears to be predictive of postpartum depression, independent of depression status before and during pregnancy. Our findings indicate that assessing the psychosocial impact of nausea and vomiting in pregnancy during antenatal care may identify women at risk of postpartum depression.

The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area.

Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000-3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure.

Investigating the impact of masculinity on the relationship between anxiety specific mental health literacy and mental health help-seeking in adolescent males.

BACKGROUND: Poor mental health literacy and greater alignment with norms of hegemonic masculinity are established barriers to mental health help-seeking in men. However, little is known about how these variables influence adolescent male help-seeking and in particular, help-seeking for anxiety disorders. This study investigated the relationship between i) anxiety mental health literacy, ii) alignment with traditional masculinity norms and iii) help-seeking attitudes, intentions and behaviour in a sample of adolescent males. METHODS: 1732 adolescent males (aged 12-18 years) participated online whilst at school. RESULTS: Participant attitudes towards formal help-seeking, intentions to seek help from a family member and from an online source were found to predict professional help-seeking behaviour by the adolescent and/or by their parents on the adolescents' behalf. In adolescents with a low or average personal alignment with norms of hegemonic masculinity, greater anxiety mental health literacy was positively associated with more favourable attitudes towards formal and informal help-seeking. However, this relationship was not found in adolescent males with a greater alignment with norms of hegemonic masculinity. LIMITATIONS: The study had a correlational research design and used self-report measures. CONCLUSIONS: Mental health initiatives which consider the impact of masculinity and gender stereotypes have the potential to significantly improve help-seeking in this population.

Genetic and Environmental Causes of Individual Differences in Borderline Personality Disorder Features and Loneliness are Partially Shared.

Loneliness is related to mental and somatic health outcomes, including borderline personality disorder. Here, we analyze the sources of variation that are responsible for the relationship between borderline personality features (including four dimensions, affective instability, identity disturbance, negative relationships, self-harm and a total score) and loneliness. Using genetically informative data from two large nonclinical samples of adult twin pairs from Australia and the Netherlands (N = 11,329), we estimate the phenotypic, genetic and environmental correlations between self-reported borderline personality features and loneliness. Individual differences in borderline personality and loneliness were best explained by additive genetic factors with heritability estimates h2 = 41% for the borderline personality total score and h2 = 36% for loneliness, with the remaining variation explained by environmental influences that were not shared by twins from the same pair. Genetic and environmental factors influencing borderline personality (total score and four subscales separately) were also partial causes of loneliness. The correlation between loneliness and the borderline personality total score was rph = .51. The genetic correlation was estimated at rg = .64 and the environmental correlation at re = .40. Our study suggests common etiological factors in loneliness and borderline personality features.

The genetic architecture of the human cerebral cortex.

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Educational attainment polygenic scores are associated with cortical total surface area and regions important for language and memory.

It is well established that higher cognitive ability is associated with larger brain size. However, individual variation in intelligence exists despite brain size and recent studies have shown that a simple unifactorial view of the neurobiology underpinning cognitive ability is probably unrealistic. Educational attainment (EA) is often used as a proxy for cognitive ability since it is easily measured, resulting in large sample sizes and, consequently, sufficient statistical power to detect small associations. This study investigates the association between three global (total surface area (TSA), intra-cranial volume (ICV) and average cortical thickness) and 34 regional cortical measures with educational attainment using a polygenic scoring (PGS) approach. Analyses were conducted on two independent target samples of young twin adults with neuroimaging data, from Australia (N â€‹= â€‹1097) and the USA (N â€‹= â€‹723), and found that higher EA-PGS were significantly associated with larger global brain size measures, ICV and TSA (R2 â€‹= â€‹0.006 and 0.016 respectively, p â€‹< â€‹0.001) but not average thickness. At the regional level, we identified seven cortical regions-in the frontal and temporal lobes-that showed variation in surface area and average cortical thickness over-and-above the global effect. These regions have been robustly implicated in language, memory, visual recognition and cognitive processing. Additionally, we demonstrate that these identified brain regions partly mediate the association between EA-PGS and cognitive test performance. Altogether, these findings advance our understanding of the neurobiology that underpins educational attainment and cognitive ability, providing focus points for future research.

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Half the Genetic Variance in Vitamin D Concentration is Shared with Skin Colour and Sun Exposure Genes.

This study assessed the heritability of 25 hydroxyvitamin D3 (25(OH)D3) in a large twin cohort and the shared effect of sun exposure and skin colour on 25(OH)D3 variance. Study participants included 1604 twin pairs and their siblings (n = 4020). Twin correlations for 25(OH)D3 concentration were rMZ=0.79 (584 pairs) and rDZ = 0.52 (1020 pairs) consistent with an average h2 = 0.50 throughout the year. Significant phenotypic and genetic seasonal fluctuation was observed in 25(OH)D3 concentrations with heritability decreasing during the winter (h2 = 0.37) compared to summer (h2 = 0.62). Skin colour (measured both ordinally and quantitatively) and self-reported sun exposure were found to significantly affect 25(OH)D3 concentration. Twins with olive/dark skin had significantly lower 25(OH)D3 concentrations than those with fair/pale skin and multivariate genetic analysis showed that approximately half of the total additive genetic variation in 25(OH)D3 results from genes whose primary influence is on skin colour and sun exposure. Additionally, 37% of the total variance was attributed to shared environmental effects on vitamin D, skin colour and sun exposure measures. These results support a moderate estimate of vitamin D heritability and suggest significant influence of season, skin colour and sun exposure on the genetic variance.

Little Evidence That Socioeconomic Status Modifies Heritability of Literacy and Numeracy in Australia.

Socioeconomic status (SES) has been found to moderate the influence of genes and the environment on cognitive ability, such that genetic influence is greater when SES is higher, and the shared environment is greater when SES is lower, but not in all Western countries. The effects of both family and school SES on the heritability of literacy and numeracy in Australian twins aged 8, 10, 12, and 14 years with 1,307, 1,235, 1,076, and 930 pairs at each age, respectively, were tested. Shared environmental influences on Grade 3 literacy were greater with low family SES, and no other moderating effects of SES were significant. These findings are contrasted with results from the United States and the United Kingdom.

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

A negative association between brainstem pontine grey-matter volume, well-being and resilience in healthy twins

Background: Associations between well-being, resilience to trauma and the volume of grey-matter regions involved in affective processing (e.g., threat/reward circuits) are largely unexplored, as are the roles of shared genetic and environmental factors derived from multivariate twin modelling. Methods: This study presents, to our knowledge, the first exploration of well-being and volumes of grey-matter regions involved in affective processing using a region-of-interest, voxel-based approach in 263 healthy adult twins (60% monozygotic pairs, 61% females, mean age 39.69 yr). To examine patterns for resilience (i.e., positive adaptation following adversity), we evaluated associations between the same brain regions and well-being in a trauma-exposed subgroup. Results: We found a correlated effect between increased well-being and reduced grey-matter volume of the pontine nuclei. This association was strongest for individuals with higher resilience to trauma. Multivariate twin modelling suggested that the common variance between the pons volume and well-being scores was due to environmental factors. Limitations: We used a cross-sectional sample; results need to be replicated longitudinally and in a larger sample. Conclusion: Associations with altered grey matter of the pontine nuclei suggest that basic sensory processes, such as arousal, startle, memory consolidation and/or emotional conditioning, may have a role in well-being and resilience.

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Estimating Heritability from Twin Studies.

This chapter describes how the heritability of a trait can be estimated using data collected from pairs of twins. The principles of the classical twin design are described, followed by the assumptions, and some possible extensions of the design. In the second part of this chapter, two example scripts are presented and the basic steps for estimating heritability using the statistical program OpenMx are explained. OpenMx and the scripts used for this chapter can be downloaded so that readers can adapt and use the scripts for their own purposes.

Preconditioning of Spatial and Auditory Cues: Roles of the Hippocampus, Frontal Cortex, and Cue-Directed Attention.

Loss of function of the hippocampus or frontal cortex is associated with reduced performance on memory tasks, in which subjects are incidentally exposed to cues at specific places in the environment and are subsequently asked to recollect the location at which the cue was experienced. Here, we examined the roles of the rodent hippocampus and frontal cortex in cue-directed attention during encoding of memory for the location of a single incidentally experienced cue. During a spatial sensory preconditioning task, rats explored an elevated platform while an auditory cue was incidentally presented at one corner. The opposite corner acted as an unpaired control location. The rats demonstrated recollection of location by avoiding the paired corner after the auditory cue was in turn paired with shock. Damage to either the dorsal hippocampus or the frontal cortex impaired this memory ability. However, we also found that hippocampal lesions enhanced attention directed towards the cue during the encoding phase, while frontal cortical lesions reduced cue-directed attention. These results suggest that the deficit in spatial sensory preconditioning caused by frontal cortical damage may be mediated by inattention to the location of cues during the latent encoding phase, while deficits following hippocampal damage must be related to other mechanisms such as generation of neural plasticity.

Genetic and Environmental Influences on Literacy and Numeracy Performance in Australian School Children in Grades 3, 5, 7, and 9.

We examined the extent to which genes and the environment contributed to variation in and covariation among reading, spelling, grammar and punctuation, writing, and numeracy in Australian school children in Grades 3, 5, 7, and 9. Heritability was generally high: reading .58-.71 (excepting Grade 5 girls), spelling .68-.78; grammar and punctuation .52-.66, writing .39-.52, and numeracy .39-.79. Boys' performance varied more than girls in spelling and numeracy, and the common environment was a greater influence in girls than boys in Grade 3 numeracy and Grade 5 reading. Independent pathway models showed similar genetic and environmental structures at each grade with approximately one third to one half of the variation in each domain due to genes that influenced all domains. The covariation among the domains was largely mediated by genes. Results suggest substantial uniformity in the environmental factors influencing these academic domains.

Longitudinal Stability and Growth in Literacy and Numeracy in Australian School Students.

We explored the genetic and environmental influence on both stability and growth in literacy and numeracy in 1927 Australian twin pairs from Grade 3 to Grade 9. Participants were tested on reading, spelling, grammar and punctuation, writing, and numeracy. In each domain, performance across time was highly correlated and this stability in performance was primary due to genes. Key findings on growth showed that reading followed a compensatory growth pattern that was largely due to genetic effects, while variation in growth in the other literacy domains was predominantly due to environmental influences. Genes and the shared environment influenced growth in numeracy for girls, while for boys it was influenced by the shared and unique environment. These results suggest that individual differences in growth of reading are primarily due to a genetically influenced developmental delay in the acquisition of necessary skills, while environmental influences, perhaps including different schools or teachers, are more important for the other domains.