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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. Improvement in the polygenic score prediction of hippocampal volume, as power in the discovery GWAS increases. PRS may be thought of as weighted‐sum scores that summarize the results of the GWAS to a given level of significance, these results show the increased explanatory power of the GWAS for hipocampal volume as sample size increases.

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 ​= ​1097) and the USA (N ​= ​723), and found that higher EA-PGS were significantly associated with larger global brain size measures, ICV and TSA (R2 ​= ​0.006 and 0.016 respectively, p ​< ​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.

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.

Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from functional, cytoarchitectural, or other cortical parcellation schemes. We investigated genetic pleiotropy by applying genomic structural equation modeling (SEM) to map the genetic architecture of cortical surface area (SA) and cortical thickness (CT) for 34 brain regions recently reported in the ENIGMA cortical GWAS. Genomic SEM uses the empirical genetic covariance estimated from GWAS summary statistics with LD score regression (LDSC) to discover factors underlying genetic covariance, which we are denoting genetically informed brain networks (GIBNs). Genomic SEM can fit a multivariate GWAS from summary statistics for each of the GIBNs, which can subsequently be used for LD score regression (LDSC). We found the best-fitting model of cortical SA identified 6 GIBNs and CT identified 4 GIBNs, although sensitivity analyses indicated that other structures were plausible. The multivariate GWASs of the GIBNs identified 74 genome-wide significant (GWS) loci ( p  < 5 × 10 − 8 ), including many previously implicated in neuroimaging phenotypes, behavioral traits, and psychiatric conditions. LDSC of GIBN GWASs found that SA-derived GIBNs had a positive genetic correlation with bipolar disorder (BPD), and cannabis use disorder, indicating genetic predisposition to a larger SA in the specific GIBN is associated with greater genetic risk of these disorders. A negative genetic correlation was observed between attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). CT GIBNs displayed a negative genetic correlation with alcohol dependence. Even though we observed model instability in our application of genomic SEM to high-dimensional data, jointly modeling the genetic architecture of complex traits and investigating multivariate genetic links across neuroimaging phenotypes offers new insights into the genetics of cortical structure and relationships to psychopathology.

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.

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.

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.

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.

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. 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. 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. We used a cross-sectional sample; results need to be replicated longitudinally and in a larger sample. 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.

New interventions are needed for obsessive-compulsive disorder. Here we present a randomized single-blinded, two-arm, parallel-group, sham-controlled clinical trial assessing the efficacy of prefrontal cortex stimulation in reducing obsessive-compulsive disorder symptoms and frontostriatal connectivity (ACTRN12616001687482). Conducted at a single academic center, the trial enrolled participants diagnosed with obsessive-compulsive disorder who underwent baseline clinical assessments and neuroimaging. The intervention comprised 20 weekday sessions of neuronavigated continuous theta burst stimulation of the frontal pole or sham. Participants and all staff assessing intervention outcomes were blind to the conditions. We enrolled a sample of 50 individuals (26 active continuous theta burst stimulation) who completed the neuroimaging and clinical assessments at the primary 4 week endpoint. Clinical data at the secondary 6 month endpoint were obtained from 46 participants (23 active). Symptoms of obsessive-compulsive disorder (primary outcome) decreased in both groups (active −4.35, P < 0.001; sham −5.92, P < 0.001), but there was no significant difference between groups (P = 0.33, ηp2 = 0.02). Likewise, there was no significant difference between groups in changes of frontal pole connectivity with the striatum (P = 0.09, ηp2 = 0.06). Changes in secondary outcomes (symptoms of anxiety and depression and localized frontal pole activity) did not differ between groups. Dropout rates did not vary between groups and the most common treatment-related adverse event in both groups was headache. Our findings suggest that frontal pole continuous theta burst stimulation is no different to sham in reducing obsessive-compulsive disorder symptoms. The absence of changes in brain activity prompts further evaluation of alternative stimulation protocols.Cocchi and coauthors report that continuous theta burst stimulation of the frontal pole shows no difference from sham in reducing symptoms of obsessive-compulsive disorder or frontostriatal connectivity.