Using rare genetic mutations to revisit structural brain asymmetry

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities

APOE alleles are associated with sex-specific structural differences in brain regions affected in Alzheimer's disease and related dementia.

Alzheimer's disease is marked by intracellular tau aggregates in the medial temporal lobe (MTL) and extracellular amyloid aggregates in the default network (DN). Here, we examined codependent structural variations between the MTL's most vulnerable structure, the hippocampus (HC), and the DN at subregion resolution in individuals with Alzheimer's disease and related dementia (ADRD). By leveraging the power of the approximately 40,000 participants of the UK Biobank cohort, we assessed impacts from the protective APOE ɛ2 and the deleterious APOE ɛ4 Alzheimer's disease alleles on these structural relationships. We demonstrate ɛ2 and ɛ4 genotype effects on the inter-individual expression of HC-DN co-variation structural patterns at the population level. Across these HC-DN signatures, recurrent deviations in the CA1, CA2/3, molecular layer, fornix's fimbria, and their cortical partners related to ADRD risk. Analyses of the rich phenotypic profiles in the UK Biobank cohort further revealed male-specific HC-DN associations with air pollution and female-specific associations with cardiovascular traits. We also showed that APOE ɛ2/2 interacts preferentially with HC-DN co-variation patterns in estimating social lifestyle in males and physical activity in females. Our structural, genetic, and phenotypic analyses in this large epidemiological cohort reinvigorate the often-neglected interplay between APOE ɛ2 dosage and sex and link APOE alleles to inter-individual brain structural differences indicative of ADRD familial risk

Societal risk factors exhibit salient association effects with social isolation.

Bayesian estimation of the posterior probability that a given risk factor relates to one of two measures of social deprivation: loneliness and lack of social support. All societal risk factor variables were z-scored prior to running the Bayesian models. For simplicity, results are expressed as the mean and the 90% highest posterior density interval for the model coefficients (black error bars). In the UKBB and the CLSA datasets, loneliness and lack of social support show strong associations with several societal factors, including (A) the number of people living in the household and the number of close friends, (B) household income, and (C) graduating from high school and obtaining higher degrees. (D) Living in an urban environment is also linked with higher levels of subjective and objective social deprivation.</p

Widespread cross-associations exist between social deprivation indicators and traditional risk factors for Alzheimer’s dementias.

To gain a synoptic overview, we initially explored multivariable relationships between sets of social richness measures (top row) and sets of usually studied aetiopathological risk factors (lower row). In 502,506 UK Biobank participants (left column), the leading explanatory patterns (‘modes’) show that perceived and objective social isolation are associated with higher neuroticism scores and similar personality styles. In 30,097 CLSA participants (right column), the dominant pattern links loneliness and lacking social support to TV consumption and depression-related emotional traits. This doubly multivariate decomposition of two variable sets was obtained from partial least squares analysis (PLS; cf. Methods). Note that this cursory analysis does not attempt to single out special variables (in contrast to the analyses from Figs 2–5). Overall, this perspective makes apparent that the majority of examined risk factors may be related to some aspect of social lifestyle.</p

Various ADRD-related lifestyle factors show strong association effects with loneliness and lack of social support across both cohorts.

Bayesian estimation of the posterior probability that a given risk factor relates to one of two measures of social deprivation: loneliness and lack of social support. All target risk factor variables were z-scored prior to running the Bayesian models. For simplicity, results are expressed as the mean and the 90% highest posterior density interval of the model coefficients (black error bars). In both UKBB and the CLSA, loneliness and lack of social support are robustly associated with a variety of lifestyle factors, including (A) current cigarette smoking, (B) alcohol consumption, (C) sleep duration, and (D) participation in physical activities with others. (E) Use of electronic devices and (F) participation in religious activities show smaller links to loneliness and weak social support. Both subjective and objective social isolation follow similar patterns in their associations with behavioural traits across the two cohorts. Sleeplessness has the largest association with social isolation in this category.</p

Mental health factors show prominent association effects with social isolation.

Bayesian estimation of the posterior probability that a given risk factor relates to one of two measures of social deprivation: loneliness and lack of social support. All target risk factor variables were normalized by z-scoring across participants prior to running the Bayesian models. For simplicity, results are expressed as the mean and the 90% highest posterior density interval for the model coefficients (black error bars). In this category and across the two datasets, both loneliness and lack of social support show some of the most prominent links with (A) depression and anxiety, (B) feelings of happiness, and (C) several measures of personality that play into the stress-buffer capacity of an individual. In particular, the neuroticism score has the largest association with both subjective and objective social isolation among all the examined ADRD risk factors.</p

Physical health factors are related to social isolation.

Bayesian estimation of the posterior probability that a given risk factor relates to one of two measures of social deprivation: loneliness and lack of social support. All physical health risk factor variables were standardized prior to running the Bayesian models. For simplicity, results are expressed as the mean and the 90% highest posterior density interval of the model coefficients (black error bars). In the UKBB and the CLSA cohorts, loneliness and poor social support show strong links with several physical health factors, such as (A) hypertension, (B) diabetes, (C) hearing difficulty with background noise, and (D) being a vision aid user. Across the two cohorts, hearing difficulty with background noise has the largest association with both subjective and objective social isolation in this pillar of risk traits.</p

Mean associations between subjective and objective social isolation and ADRD risk factors in the UKBB and the CLSA.

Mean associations between subjective and objective social isolation and ADRD risk factors in the UKBB and the CLSA.</p

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Using rare genetic mutations to revisit structural brain asymmetry.

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely&nbsp;human cognitive capacities