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Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth.Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers.Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms.Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits.

The genetic architecture of testosterone is highly distinct between sexes. Moreover, obesity is associated with higher testosterone in females but lower testosterone in males. Here, we ask whether male-specific testosterone variants are associated with a male pattern of obesity and type 2 diabetes (T2D) in females, and vice versa. In the UK Biobank, we conducted sex-specific genome-wide association studies and computed polygenic scores for total (PGSTT) and bioavailable testosterone (PGSBT). We tested sex-congruent and sex-incongruent associations between sex-specific PGSTs and metabolic traits, as well as T2D diagnosis. Female-specific PGSBT was associated with an elevated cardiometabolic risk and probability of T2D, in both sexes. Male-specific PGSTT was associated with traits conferring a lower cardiometabolic risk and probability of T2D, in both sexes. We demonstrate the value in considering polygenic testosterone as sex-related continuous traits, in each sex.

Context Sex hormone-binding globulin (SHBG) is associated with levels of total testosterone (total-T), and both total-T and SHBG are associated with obesity. Objective We aimed to clarify the nature of the relationship between testosterone and SHBG and improve our understanding of their relationships with obesity. We hypothesize that the hypothalamic-pituitary-gonadal axis contributes to the homeostasis of testosterone by increasing the production of gonadal testosterone through a feedback mechanism that might operate differently at different pubertal stages. Methods We investigated the dynamics of the relationship between SHBG, total-T, and body mass index (BMI) throughout puberty (from age 9 to 17) using longitudinal data obtained in 507 males. The directionality of this relationship was explored using polygenic scores of SHBG and total-T, and a two-sample Mendelian Randomization (MR) in male adults. Results Consistent with our hypothesis, we found positive relationships between SHBG and total-T at age 15 and 17 but either no relationship or a negative relationship during the earlier time points. Such shifting relationships explained age-related changes in the association between total-T and BMI. Polygenic scores of SHBG and total-T in mediation analyses and the two-sample MR in male adults suggested an effect of SHBG on total-T but also a somewhat weaker effect of total-T on SHBG. Two-sample MR also showed an effect of BMI on SHBG but no effect of SHBG on BMI. Conclusion These results clarify the nature of the relationship between testosterone and SHBG during puberty and adulthood and shed new light on their possible relationship with obesity.

Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.

Objective Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC+/- mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC+/- mutation carriers without mirror movements might exhibit some of these features. Methods The participants (n = 52) included 13 DCC+/- mutation carriers with mirror movements, 7 DCC+/- mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity. Results Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS-induced motor evoked potentials, increased fMRI responses in the mirroring M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC+/- mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity. Interpretation Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype. ANN NEUROL 2019;85:433-442.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade—albeit in a very limited manner—to behaviors as complex as the choice of one’s occupation.

Many traits of the brain and body show marked sex differences, but the distributions of their values overlap substantially between the two sexes. To investigate variations associated with biological sex, beyond binary differences, we create continuous sex scores capturing the inter-individual variability in phenotypes. In an adolescent cohort (n = 1,029; 533 females), we have generated three sex scores based on brain-body traits: 'overall' (48 traits), 'pubertal' (26 traits) and 'non-pubertal' (22 traits). We then conducted sex-stratified multiple linear regressions (adjusting for age) using sex scores to test associations with sex hormones, personality traits and internalizing-externalizing behaviour. Higher sex scores (that is, greater 'femaleness') were associated with lower testosterone in males only, as well as lower extraversion, higher internalizing and lower externalizing in both sexes. The associations with testosterone, internalizing and externalizing were driven by pubertal sex scores, underscoring the importance of adolescence in shaping within-sex individual variability.

The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected inDcc-haploinsufficient mice. The human volunteers were 20DCC+/−mutation carriers, 16DCC+/+relatives, and 20DCC+/+unrelated healthy volunteers (UHVs; 28 females). The mice were 11Dcc+/−and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the humanDCC+/−carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+:p= 0.0005,r(effect size) = 0.60; UHV:p= 0.0029,r= 0.48] and ventral medial prefrontal cortex (DCC+/+:p= 0.0031,r= 0.53; UHV:p= 0.034,r= 0.35); (2) lower novelty-seeking scores (DCC+/+:p= 0.034,d= 0.82; UHV:p= 0.019,d= 0.84); and (3) reduced striatal volume (DCC+/+:p= 0.0009,d= 1.37; UHV:p= 0.0054,d= 0.93). Striatal volumetric reductions were also present inDcc+/−mice, and these were seen during adolescence (p= 0.0058,d= 1.09) and adulthood (p= 0.003,d= 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through whichDCCmutations might affect susceptibility to diverse neuropsychiatric disorders.SIGNIFICANCE STATEMENTOpportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene,DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated inDCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.

The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc-haploinsufficient mice. The human volunteers were 20 DCC+/− mutation carriers, 16 DCC+/+ relatives, and 20 DCC+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc+/− and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC+/− carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+: p = 0.0005, r(effect size) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex (DCC+/+: p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores (DCC+/+: p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume (DCC+/+: p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc+/− mice, and these were seen during adolescence (p = 0.0058, d = 1.09) and adulthood (p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.