Brain reserve in midlife is associated with executive function changes across 12 years.

We examined how brain reserve in midlife, measured by brain-predicted age difference scores (Brain-PADs), predicted executive function concurrently and longitudinally into early old age, and whether these associations were moderated by young adult cognitive reserve or APOE genotype. 508 men in the Vietnam Era Twin Study of Aging (VETSA) completed neuroimaging assessments at mean age 56 and six executive function tasks at mean ages 56, 62, and 68 years. Results indicated that greater brain reserve at age 56 was associated with better concurrent executive function (r=.10, p=.040) and less decline in executive function over 12 years (r=.34, p=.001). These associations were not moderated by cognitive reserve or APOE genotype. Twin analysis suggested associations with executive function slopes were driven by genetic influences. Our findings suggest that greater brain reserve allowed for better cognitive maintenance from middle- to old age, driven by a genetic association. The results are consistent with differential preservation of executive function based on brain reserve that is independent of young adult cognitive reserve or APOE genotype.

Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men.

BACKGROUND: Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations. METHODS: We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter. RESULTS: After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals. CONCLUSIONS: These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Midlife cumulative deficit frailty predicts Alzheimer's disease-related plasma biomarkers in older adults.

BACKGROUND: The study explores whether frailty at midlife predicts mortality and levels of biomarkers associated with Alzheimer's disease and related dementias (ADRD) and neurodegeneration by early old age. We also examine the heritability of frailty across this age period. METHODS: Participants were 1,286 community-dwelling men from the Vietnam Era Twin Study of Aging at average ages 56, 62 and 68, all without ADRD at baseline. The cumulative deficit frailty index (FI) comprised 37 items assessing multiple physiological systems. Plasma biomarkers at age 68 included beta-amyloid (Aß40, Aß42), total tau (t-tau) and neurofilament light chain (NfL). RESULTS: Being frail doubled the risk of all-cause mortality by age 68 (OR = 2.44). Age 56 FI significantly predicted age 68 NfL (P = 0.014), Aß40 (P = 0.001) and Aß42 (P = 0.023), but not t-tau. Age 62 FI predicted all biomarkers at age 68: NfL (P = 0.023), Aß40 (P = 0.002), Aß42 (P = 0.001) and t-tau (P = 0.001). Age 68 FI scores were associated with age 68 levels of NfL (P = 0.027), Aß40 (P < 0.001), Aß42 (P = 0.001) and t-tau (P = 0.003). Genetic influences accounted for 45-48% of the variance in frailty and significantly contributed to its stability across 11 years. CONCLUSIONS: Frailty during one's 50s doubled the risk of mortality by age 68. A mechanism linking frailty and ADRD may be through its associations with biomarkers related to neurodegeneration. Cumulative deficit frailty increases with age but remains moderately heritable across the age range studied. With environmental factors accounting for about half of its variance, early interventions aimed at reducing frailty may help to reduce risk for ADRD.

The heritability of blood-based biomarkers related to risk of Alzheimer's disease in a population-based sample of early old-age men.

INTRODUCTION: Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. METHODS: Plasma amyloid beta 40 (Aß40), Aß42, the Aß42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (µ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. RESULTS: Additive genetics explained 44% to 52% of Aß42, Aß40, t-tau, and NfL. The Aß42/40 ratio was not heritable. Aß40 and Aß42 were genetically near identical (rg  = 0.94). Both Aß40 and Aß42 were genetically correlated with NfL (rg  = 0.35 to 0.38), but genetically unrelated to t-tau. DISCUSSION: Except for Aß42/40, plasma biomarkers are heritable. Aß40 and Aß42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aßs and t-tau is not consistent with the amyloid cascade hypothesis.

A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

Polygenic risk scores and the prediction of onset of mood and psychotic disorders in adolescents and young adults.

AIM: To examine whether polygenic risk scores (PRS) for neuroticism, depression, bipolar disorder and schizophrenia are higher in individuals manifesting trans-diagnostic risk factors for the development of major mental disorders and whether PRS enhance prediction of early onset full-threshold disorders. METHODS: Using data from the Brisbane Longitudinal Twin Study, we examined individual PRS for neuroticism, depression, bipolar disorder and schizophrenia, recorded evidence of subthreshold syndromes and family history of mood and/or psychotic disorders and noted progression to trans-diagnostic clinical caseness (onset of major mental disorders) at follow-up. We undertook multivariate, receiver operating curve and logistic regression analyses that were adjusted for known variables of influence (age, twin status, and so on). RESULTS: Of 1473 eligible participants (female = 866, 59%; mean age 26.3 years), 28% (n = 409) met caseness criteria for a mood and/or psychotic disorder. All PRS were higher in cases versus non-cases but associations with different levels of risk were inconsistent. The prediction of caseness (reported as area under the curve with 95% confidence intervals [CI]) improved from 0.68 (95% CI: 0.65, 0.71) when estimated using clinical risk factors alone up to 0.71 (95% CI: 0.69, 0.73) when PRS were added to the model. Logistic regression identified five variables that optimally classified individuals according to caseness: age, sex, individual risk characteristics, PRS for depression and mental health case status of cotwins or siblings. CONCLUSIONS: The findings need replication. However, this exploratory study suggests that combining PRS with other risk factors has the potential to improve outcome prediction in youth.

Associations of polygenic risk scores for smoking heaviness and lifetime cannabis use with tobacco and cannabis co-use trajectories among African Americans.

BACKGROUND: We aimed to identify distinct trajectories of tobacco, cannabis, and their co-use among African Americans, and to investigate whether these patterns were associated with polygenic risk scores (PRS) for tobacco and cannabis use. METHOD: Participants (N=428 participants; 50.9% male) were initially recruited for an elementary school-based prevention in a Mid-Atlantic city when they were in first grade. From ages 14-26, participants reported on their frequency of tobacco and cannabis use in the past year during annual assessments. DNA was collected from participants at age 21. PRS for smoking heaviness (i.e., cigarettes per day) and lifetime cannabis use were created based on genome-wide association study results derived from Liu et al. (2019) and Pasman et al. (2018), respectively. RESULTS: We identified five distinct trajectories of tobacco and cannabis co-use, including (1) Low Tobacco and Cannabis Use, (2) Adolescent Limited Tobacco and Cannabis Use, (3) Experimental Cannabis, Young Adult Increasing Tobacco, (4) Experimental Tobacco, Young Adult Increasing Cannabis, and (5) High, Chronic Tobacco and Cannabis Use. Compared to the Low Tobacco and Cannabis Use subgroup, individuals in the High, Chronic Tobacco and Cannabis Use subgroup had greater PRS for smoking heaviness, and individuals in the Experimental Cannabis, Young Adult Increasing Tobacco subgroup had higher PRS for lifetime cannabis use. CONCLUSIONS: Polygenic risk for lifetime cannabis use and smoking heaviness is associated with the developmental progression of tobacco and cannabis co-use among African Americans, furthering knowledge on the etiology of co-use in this population.

Higher cortical thickness/volume in Alzheimer's-related regions: protective factor or risk factor?

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51-60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.

A Traitlike Dimension of Subjective Memory Concern Over 30 Years Among Adult Male Twins.

Importance: Subjective memory concern has long been considered a state-related indicator of impending cognitive decline or dementia. The possibility that subjective memory concern may itself be a heritable trait is largely ignored, yet such an association would substantially confound its use in clinical or research settings. Objective: To assess the heritability and traitlike dimensions of subjective memory concern and its clinical correlates. Design, Setting, and Participants: This longitudinal twin cohort study was conducted from 1967 to 2019 among male adults with a mean (SD) age of 37.75 (2.52) years to follow-up at mean ages of 56.15 (2.72), 61.50 (2.43), and 67.35 (2.57) years (hereafter, 38, 56, 62, and 67 years, respectively) in the Vietnam Era Twin Study of Aging. The study included a national community-dwelling sample with health, education, and lifestyle characteristics comparable to a general sample of US men in this age cohort. Participants were monozygotic and dizygotic twins randomly recruited from the Vietnam Era Twin Registry. Data were analyzed from May 2021 to December 2022. Main Outcomes and Measures: Measures included subjective memory concern at 4 time points; objective memory, depressive symptoms, and anxiety at the last 3 time points; negative emotionality (trait neuroticism) at age 56 years; polygenic risk scores (PRSs) for neuroticism, depression, and Alzheimer disease; APOE genotype; and parental history of dementia. Primary outcomes were heritability and correlations between subjective memory concern and other measures. Results: The sample included 1555 male adults examined at age 38 years, 520 at age 56 years (due to late introduction of subjective memory concern questions), 1199 at age 62 years, and 1192 at age 67 years. Phenotypically, subjective memory concerns were relatively stable over time. At age 56 years, subjective memory concern had larger correlations with depressive symptoms (r, 0.32; 95% CI, 0.21 to 0.42), anxiety (r, 0.36; 95% CI, 0.18 to 0.51), and neuroticism (r, 0.34; 95% CI, 0.26 to 0.41) than with objective memory (r, -0.24; 95% CI, -0.33 to -0.13). Phenotypic results were similar at ages 62 and 67 years. A best-fitting autoregressive twin model indicated that genetic influences on subjective memory concern accumulated and persisted over time (h2 = 0.26-0.34 from age 38-67 years). At age 56 years, genetic influences for subjective memory concern were moderately correlated with genetic influences for anxiety (r, 0.36; 95% CI, 0.18 to 0.51), negative emotionality (r, 0.51; 95% CI, 0.44-0.57), and depressive symptoms (r, 0.20; 95% CI, 0.10 to 0.29) as well as objective memory (r, -0.22; 95% CI, -0.30 to -0.14). Similar genetic correlations were seen at ages 62 and 67 years. The neuroticism PRS was associated with subjective memory concern at age 38 years (r, 0.10; 95% CI, 0.03. to 0.18) and age 67 years (r, 0.09; 95% CI, 0.01 to 0.16). Subjective memory concern was not associated with any Alzheimer disease risk measures. Conclusions and Relevance: This cohort study found stable genetic influences underlying subjective memory concern dating back to age 38 years. Subjective memory concern had larger correlations with affect-related measures than with memory-related measures. Improving the utility of subjective memory concern as an indicator of impending cognitive decline and dementia may depend on isolating its statelike component from its traitlike component.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

Is pre-college interpersonal trauma associated with cannabis use?

OBJECTIVE: To examine the prevalence and correlates of lifetime cannabis use (i.e., experimental [use 1-5 times] and non-experimental [use ≥ 6 times]) in relation to interpersonal trauma (IPT) above and beyond relevant covariates. PARTICIPANTS: A large (n = 9,889) representative sample of college students at an urban university in the southeastern part of the United States. METHODS: Participants were 4 cohorts of first-year college students who completed measures of demographics, cannabis, alcohol, nicotine, and IPT. Associations were estimated using multinomial logistic regressions. RESULTS: The prevalence of lifetime cannabis use was 28.1% and 17.4% for non-experimental and experimental cannabis use, respectively. IPT was significantly associated with experimental and non-experimental cannabis use above and beyond effects of sex, race, cohort, alcohol, and nicotine. CONCLUSIONS: Results show that cannabis use is prevalent among college students and is associated with IPT above and beyond associations with sex, race, and other substance use.

A longitudinal mediational investigation of risk pathways among cannabis use, interpersonal trauma exposure, and trauma-related distress.

OBJECTIVE: College students are at high risk for cannabis use, interpersonal trauma (IPT) exposure, and trauma-related distress (TRD). Two phenotypic etiologic models posited to explain associations between cannabis use and trauma-related phenotypes are the self-medication (trauma/TRD → cannabis use) and high-risk (cannabis use → trauma/TRD) hypotheses. The primary objective of the present study was to investigate direct and indirect associations among cannabis use, IPT exposure, and TRD above and beyond established covariates. METHOD: The current study used data from the first assessment (i.e., baseline survey at Year 1 Fall) and two follow-up assessments (i.e., Year 1 Spring and Year 2 Spring) from an ongoing longitudinal study on college behavioral health. Participants were 4 cohorts of college students (n = 9,889) who completed measures of demographics, substance use, IPT, and TRD. Indirect effects of IPT on cannabis through TRD (i.e., self-medication) and cannabis on TRD through IPT (i.e., high-risk), including tests of covariate effects (e.g., gender, age, race, cohort, alcohol, nicotine), were simultaneously estimated using a longitudinal mediation modeling framework. RESULTS: Results suggest that more IPT exposure increases risk for TRD and subsequent nonexperimental (use 6+ times) cannabis use, and that experimental (use 1-5 times) and nonexperimental cannabis use increases risk for IPT exposure and subsequent TRD. CONCLUSIONS: Both the self-medication and high-risk hypotheses were supported. Findings support a bidirectional causal relationship between cannabis use and trauma-related phenotypes. Additionally, results highlight areas for colleges to intervene among students to help reduce cannabis use and create a safer environment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Alcohol use and cognitive aging in middle-aged men: The Vietnam Era Twin Study of Aging.

OBJECTIVE: To determine associations of alcohol use with cognitive aging among middle-aged men. METHOD: 1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003-2007 to 2016-2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1-4 drinks in past 14 days), light (5-14 drinks), moderate (15-28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors. RESULTS: Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by -0.21 SD (95% CI -0.35, -0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, -0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association. CONCLUSIONS: Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.

Genetic and Environmental Influences on Structural and Diffusion-Based Alzheimer's Disease Neuroimaging Signatures Across Midlife and Early Old Age.

BACKGROUND: Composite scores of magnetic resonance imaging-derived metrics in brain regions associated with Alzheimer's disease (AD), commonly termed AD signatures, have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared with thickness/volume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities and whether diffusion- and thickness/volume-based signatures each capture unique AD-related phenotypic or genetic information remains unknown. METHODS: Our validated thickness/volume signature, our novel mean diffusivity (MD) signature, and a magnetic resonance imaging-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) (baseline/wave 1: mean age [years] = 56.1, SD = 2.6, range = 51.1-60.2). Subsequent waves occurred at approximately 5.7-year intervals. RESULTS: MD and thickness/volume signatures were highly heritable (56%-72%). Baseline MD signatures predicted thickness/volume signatures over a decade later, but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance. CONCLUSIONS: Cortical MD and thickness/volume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk.

Association of neurofilament light chain with renal function: mechanisms and clinical implications.

BACKGROUND: Blood-based neurofilament light chain (NfL) is a promising biomarker of neurodegeneration across multiple neurodegenerative diseases. However, blood-based NfL is highly associated with renal function in older adults, which leads to the concern that blood-based NfL levels may be influenced by renal function, rather than neurodegeneration alone. Despite growing interest in using blood-based NfL as a biomarker of neurodegeneration in research and clinical practices, whether renal function should always be accounted for in these settings remains unclear. Moreover, the mechanisms underlying this association between blood-based measures of NfL and renal function remain elusive. In this study, we first evaluated the effect of renal function on the associations of plasma NfL with other measures of neurodegeneration. We then examined the extent of genetic and environmental contributions to the association between plasma NfL and renal function. METHODS: In a sample of 393 adults (mean age=75.22 years, range=54-90), we examined the associations of plasma NfL with cerebrospinal fluid (CSF) NfL and brain volumetric measures before and after adjusting for levels of serum creatinine (an index of renal function). In an independent sample of 969 men (mean age=67.57 years, range=61-73) that include monozygotic and dizygotic twin pairs, we replicated the same analyses and leveraged biometrical twin modeling to examine the genetic and environmental influences on the plasma NfL and creatinine association. RESULTS: Plasma NfL's associations with cerebrospinal fluid NfL and brain volumetric measures did not meaningfully change after adjusting for creatinine levels. Both plasma NfL and creatinine were significantly heritable (h2=0.54 and 0.60, respectively). Their phenotypic correlation (r=0.38) was moderately explained by shared genetic influences (genetic correlation=0.46) and unique environmental influences (unique environmental correlation=0.27). CONCLUSIONS: Adjusting for renal function is unnecessary when assessing associations between plasma NfL and other measures of neurodegeneration but is necessary if plasma NfL is compared to a cutoff for classifying neurodegeneration-positive versus neurodegeneration-negative individuals. Blood-based measures of NfL and renal function are heritable and share common genetic influences.

Examining the source of increased bipolar disorder and major depressive disorder common risk variation burden in multiplex schizophrenia families.

Psychotic and affective disorders often aggregate in the relatives of probands with schizophrenia, and genetic studies show substantial genetic correlation among schizophrenia, bipolar disorder, and major depressive disorder. In this study, we examined the polygenic risk burden of bipolar disorder and major depressive disorder in 257 multiplex schizophrenia families (N = 1005) from the Irish Study of High-Density Multiplex Schizophrenia Families versus 2205 ancestry-matched controls. Our results indicate that members of multiplex schizophrenia families have an increased polygenic risk for bipolar disorder and major depressive disorder compared to population controls. However, this observation is largely attributable to the part of the genetic risk that bipolar disorder or major depressive disorder share with schizophrenia due to genetic correlation, rather than the affective portion of the genetic risk unique to them. These findings suggest that a complete interpretation of cross-disorder polygenic risks in multiplex families requires an assessment of the relative contribution of shared versus unique genetic factors to account for genetic correlations across psychiatric disorders.

The genetic aetiology of cannabis use: from twin models to genome-wide association studies and beyond.

Cannabis is among the most widely consumed psychoactive substances worldwide. Individual differences in cannabis use phenotypes can partly be explained by genetic differences. Technical and methodological advances have increased our understanding of the genetic aetiology of cannabis use. This narrative review discusses the genetic literature on cannabis use, covering twin, linkage, and candidate-gene studies, and the more recent genome-wide association studies (GWASs), as well as the interplay between genetic and environmental factors. Not only do we focus on the insights that these methods have provided on the genetic aetiology of cannabis use, but also on how they have helped to clarify the relationship between cannabis use and co-occurring traits, such as the use of other substances and mental health disorders. Twin studies have shown that cannabis use is moderately heritable, with higher heritability estimates for more severe phases of use. Linkage and candidate-gene studies have been largely unsuccessful, while GWASs so far only explain a small portion of the heritability. Dozens of genetic variants predictive of cannabis use have been identified, located in genes such as CADM2, FOXP2, and CHRNA2. Studies that applied multivariate methods (twin models, genetic correlation analysis, polygenic score analysis, genomic structural equation modelling, Mendelian randomisation) indicate that there is considerable genetic overlap between cannabis use and other traits (especially other substances and externalising disorders) and some evidence for causal relationships (most convincingly for schizophrenia). We end our review by discussing implications of these findings and suggestions for future work.

Determining the stability of genome-wide factors in BMI between ages 40 to 69 years.

Genome-wide association studies (GWAS) have successfully identified common variants associated with BMI. However, the stability of aggregate genetic variation influencing BMI from midlife and beyond is unknown. By analysing 165,717 men and 193,073 women from the UKBiobank, we performed BMI GWAS on six independent five-year age intervals between 40 and 72 years. We then applied genomic structural equation modeling to test competing hypotheses regarding the stability of genetic effects for BMI. LDSR genetic correlations between BMI assessed between ages 40 to 73 were all very high and ranged 0.89 to 1.00. Genomic structural equation modeling revealed that molecular genetic variance in BMI at each age interval could not be explained by the accumulation of any age-specific genetic influences or autoregressive processes. Instead, a common set of stable genetic influences appears to underpin genome-wide variation in BMI from middle to early old age in men and women alike.