Shared Genetic Basis Research Articles

Single-nucleotide polymorphisms and haplotypes in the interleukin-33 gene are associated with a risk of allergic rhinitis in the Chinese population.

Allergic rhinitis (AR) is a common upper airway disease attributed to a variety of risk factors, such as environmental exposures and genetic susceptibility. The commonly observed comorbidity of asthma and AR in the clinic suggests the presence of shared genetic risk factors and biological mechanisms between these diseases. Interleukin (IL)-33 has been indicated to be an important factor driving asthma susceptibility and pathogenesis using both genome-wide association studies and functional studies in model animals. Although previous studies have reported the putative association of this gene with AR, evidence for the association of genetic variations of IL-33 with the disease is still missing. To examine whether variations in the IL-33 gene confer a genetic risk of AR, a total of 769 patients with AR and 769 age- and sex-matched healthy controls were recruited among Han Chinese residents in the Hubei province, and 14 single-nucleotide polymorphisms (SNPs) spanning the IL-33 gene were examined for their association with the risk of AR. The results indicated that five SNPs, which were in a moderate linkage disequilibrium and were located in the 5'-flanking region of IL-33, exhibited significant associations with the risk of AR, and these associations were additionally supported by genotypic and haplotypic analyses. Notably, three of the five IL-33 SNPs have been previously reported to exhibit genome-wide associations with asthma, and their alleles were also revealed to confer an increased risk of AR in the present study. In summary, the results of the current study suggested that certain variations in the IL-33 gene represent a potential risk for AR, and indicated a shared genetic basis between AR and asthma.

Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

Common Susceptibility Loci for Male Breast Cancer.

BackgroundThe etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10–06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.ResultsThe genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10–08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor–positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10–30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Genomics of sex allocation in the parasitoid wasp Nasonia vitripennis

BackgroundWhilst adaptive facultative sex allocation has been widely studied at the phenotypic level across a broad range of organisms, we still know remarkably little about its genetic architecture. Here, we explore the genome-wide basis of sex ratio variation in the parasitoid wasp Nasonia vitripennis, perhaps the best studied organism in terms of sex allocation, and well known for its response to local mate competition.ResultsWe performed a genome-wide association study (GWAS) for single foundress sex ratios using iso-female lines derived from the recently developed outbred N. vitripennis laboratory strain HVRx. The iso-female lines capture a sample of the genetic variation in HVRx and we present them as the first iteration of the Nasonia vitripennis Genome Reference Panel (NVGRP 1.0). This panel provides an assessment of the standing genetic variation for sex ratio in the study population. Using the NVGRP, we discovered a cluster of 18 linked SNPs, encompassing 9 annotated loci associated with sex ratio variation. Furthermore, we found evidence that sex ratio has a shared genetic basis with clutch size on three different chromosomes.ConclusionsOur approach provides a thorough description of the quantitative genetic basis of sex ratio variation in Nasonia at the genome level and reveals a number of inter-related candidate loci underlying sex allocation regulation.

Personality and local brain structure: Their shared genetic basis and reproducibility

Local cortical architecture is highly heritable and distinct genes are associated with specific cortical regions. Total surface area has been shown to be genetically correlated with complex cognitive capacities, suggesting cortical brain structure is a viable endophenotype linking genes to behavior. However, to what extend local brain structure has a genetic association with cognitive and emotional functioning is incompletely understood. Here, we study the genetic correlation between personality traits and local cortical structure in a large-scale twin sample (Human Connectome Project, n ​= ​1102, 22-37y) and we evaluated whether observed associations reflect generalizable relationships between personality and local brain structure two independent age-matched samples (Brain Genomics Superstructure Project: n ​= ​925, age ​= ​19-35y, enhanced Nathan Kline Institute dataset: n ​= ​209, age: 19-39y). We found a genetic overlap between personality traits and local cortical structure in 10 of 18 observed phenotypic associations in predominantly frontal cortices. However, we only observed evidence in favor of replication for the negative association between surface area in medial prefrontal cortex and Neuroticism in both replication samples. Quantitative functional decoding indicated this region is implicated in emotional and socio-cognitive functional processes. In sum, our observations suggest that associations between local brain structure and personality are, in part, under genetic control. However, associations are weak and only the relation between frontal surface area and Neuroticism was consistently observed across three independent samples of young adults.

Unique Genomic and Phenotypic Responses to Extreme and Variable pH Conditions in Purple Urchin Larvae.

Environmental variation experienced by a species across space and time can promote the maintenance of genetic diversity that may be adaptive in future global change conditions. Selection experiments have shown that purple sea urchin, Strongylocentrotus purpuratus, populations have adaptive genetic variation for surviving pH conditions at the "edge" (pH 7.5) of conditions experienced in nature. However, little is known about whether populations have genetic variation for surviving low-pH events beyond those currently experienced in nature or how variation in pH conditions affects organismal and genetic responses. Here, we quantified survival, growth, and allele frequency shifts in experimentally selected developing purple sea urchin larvae in static and variable conditions at three pH levels: pH 8.1 (control), pH 7.5 (edge-of-range), and pH 7.0 (extreme). Variable treatments recovered body size relative to static treatments, but resulted in higher mortality, suggesting a potential tradeoff between survival and growth under pH stress. However, within each pH level, allele frequency changes were overlapping between static and variable conditions, suggesting a shared genetic basis underlying survival to mean pH regardless of variability. In contrast, genetic responses to pH 7.5 (edge) versus pH 7.0 (extreme) conditions were distinct, indicating a unique genetic basis of survival. In addition, loci under selection were more likely to be in exonic regions than regulatory, indicating that selection targeted protein-coding variation. Loci under selection in variable pH 7.5 conditions, more similar to conditions periodically experienced in nature, performed functions related to lipid biosynthesis and metabolism, while loci under selection in static pH 7.0 conditions performed functions related to transmembrane and mitochondrial processes. While these results are promising in that purple sea urchin populations possess genetic variation for surviving extreme pH conditions not currently experienced in nature, they caution that increased acidification does not result in a linear response but elicits unique physiological stresses and survival mechanisms.

Shared and Independent Genetic Basis of Resistance to Bt Toxin Cry2Ab in Two Strains of Pink Bollworm

Evolution of pest resistance threatens the benefits of crops genetically engineered to produce insecticidal proteins from Bacillus thuringiensis (Bt). Field populations of the pink bollworm (Pectinophora gossypiella), a global pest of cotton, have evolved practical resistance to transgenic cotton producing Bt toxin Cry2Ab in India, but not in the United States. Previous results show that recessive mutations disrupting an autosomal ATP-binding cassette gene (PgABCA2) are associated with pink bollworm resistance to Cry2Ab in field-selected populations from India and in one lab-selected strain from the United States (Bt4-R2). Here we discovered that an independently derived, lab-selected Cry2Ab-resistant pink bollworm strain from the United States (BX-R) also harbors mutations that disrupt PgABCA2. Premature stop codons introduced by mis-splicing of PgABCA2 pre-mRNA were prevalent in field-selected larvae from India and in both lab-selected strains. The most common mutation in field-selected larvae from India was also detected in both lab-selected strains. Results from interstrain crosses indicate BX-R has at least one additional mechanism of resistance to Cry2Ab that does not involve PgABCA2 and is not completely recessive or autosomal. We conclude that recessive mutations disrupting PgABCA2 are the primary, but not the only, mechanism of resistance to Cry2Ab in pink bollworm.

Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache.

BackgroundNearly a fifth of the world’s population suffer from migraine headache, yet risk factors for this disease are poorly characterized.MethodsTo further elucidate these factors, we conducted a genetic correlation analysis using cross-trait linkage disequilibrium (LD) score regression between migraine headache and 47 traits from the UK Biobank. We then tested for possible causality between these phenotypes and migraine, using Mendelian randomization. In addition, we attempted replication of our findings in an independent genome-wide association study (GWAS) when available.ResultsWe report multiple phenotypes with genetic correlation (P < 1.06 × 10−3) with migraine, including heart disease, type 2 diabetes, lipid levels, blood pressure, autoimmune and psychiatric phenotypes. In particular, we find evidence that blood pressure directly contributes to migraine and explains a previously suggested causal relationship between calcium and migraine.ConclusionsThis is the largest genetic correlation analysis of migraine headache to date, both in terms of migraine GWAS sample size and the number of phenotypes tested. We find that migraine has a shared genetic basis with a large number of traits, indicating pervasive pleiotropy at migraine-associated loci.

Heritability of objectively assessed and self-reported sedentary behavior.

Understanding the sources of the large individual differences in sedentary behavior is of great importance as this behavior is associated with pre‐mature mortality and non‐communicable diseases. Here, we report on the contribution of genetic and environmental factors to the variation in objectively assessed (accelerometer) sedentary behavior and self‐reported sitting and their shared genetic basis. In addition, the overlap of the genetic risk factors influencing sedentary time and moderate‐to‐vigorous physical activity (MVPA) was estimated. A sample of 800 individuals (twins and their siblings) was equipped with an Actigraph accelerometer for 7 days and reported on their sitting time and time spent on MVPA on those days using the IPAQ‐SF. Genetic factors explained 56% (CI: 44%, 65%) of the individual differences in objective sedentary behavior (Actigraph) and 26% (CI: 0%, 51%) of the individual differences in self‐reported sedentary behavior (IPAQ‐SF). A modest correlation (0.33) was found between these measures, which was for 45% accounted for by genetic influences. The genetic correlation was 0.49 reflecting a partly overlapping set of genes that influenced both measurements. A modest correlation (−0.27) between Actigraph‐derived sedentary time and MVPA was found, which was 13% accounted for by genetic effects. The genetic correlation was −0.31, indicating that there are overlapping genetic variants that increase sedentary time and decrease MVPA or vice versa. To conclude, more than half of the individual differences in objective sedentary time could be attributed to genetic differences, while for self‐reported sitting this was much lower. In addition, using objective measurements, this study confirms that sedentary time is not simply the inverse of MVPA. Future studies are needed to understand the pathways translating genomic variation into variation in these behaviors and how this knowledge might feed into the development of health promotion interventions.

Two novel pleiotropic loci associated with osteoporosis and abdominal obesity.

Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNP rs73134637, p = 3.45 × 10-7) and 10p14 (lead SNP rs2892347, p = 2.63 × 10-7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10-3, N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10-7) was negatively associated with PRKCQ expression in visceral adipose tissue (N = 313, p = 0.04) and in lymphocytes (N = 117, p = 0.03). As a proof-of-principle experiment, the function of rs11254759, which is 235kb 5'-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10-7) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10-3). Mendelian randomization analysis demonstrated that both FNK-BMD and TFMadj were causally associated with fracture risk (p = 1.26 × 10-23 and 1.18 × 10-11). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.

Role of rs454214 in Personality mediated Depression and Subjective Well-being

Happiness and depression are interlinked and both heritable, while personality, as an important predictor of them, shares the genetic basis with them. We conjecture that genetic factors of depression can affect both depressive symptoms (DS) and subjective well-being (SWB), while personality traits play important roles in mediating this process. In this study, 878 Han Chinese college freshmen and 384 Han Chinese patients with the major depressive disorder (MDD) were included. SNPs were genotyped using AGENA MassARRAY iPLEX technology and we investigated an important MDD variant rs454214. Correlation, association and mediation analysis were employed, aiming to decipher the complex relationship between SWB, DS, personality traits and the genetic variant. Association study indicated that rs454214 was not only associated with both SWB and DS (P < 0.05), but also possibly linked to MDD. Mediational analysis showed that rs454214 had no direct effect on SWB and DS, but had a significant indirect effect through personality traits, i.e., Extraversion, Neuroticism, Agreeableness and Openness to Experience or SWB, Extraversion, Neuroticism and Agreeableness for DS. This study found a shared genetic basis for happiness and depression; the causal process could be better explained if personality traits are taken as mediating factors.

TGF-β-driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse model.

Duchenne muscular dystrophy (DMD) is a chronic muscle disease characterized by poor myogenesis and replacement of muscle by extracellular matrix. Despite the shared genetic basis, severity of these deficits varies among patients. One source of these variations is the genetic modifier that leads to increased TGF-β activity. While anti-TGF-β therapies are being developed to target muscle fibrosis, their effect on the myogenic deficit is underexplored. Our analysis of in vivo myogenesis in mild (C57BL/10ScSn-mdx/J and C57BL/6J-mdxΔ52) and severe DBA/2J-mdx (D2-mdx) dystrophic models reveals no defects in developmental myogenesis in these mice. However, muscle damage at the onset of disease pathology, or by experimental injury, drives up TGF-β activity in the severe, but not in the mild, dystrophic models. Increased TGF-β activity is accompanied by increased accumulation of fibroadipogenic progenitors (FAPs) leading to fibro-calcification of muscle, together with failure of regenerative myogenesis. Inhibition of TGF-β signaling reduces muscle degeneration by blocking FAP accumulation without rescuing regenerative myogenesis. These findings provide in vivo evidence of early-stage deficit in regenerative myogenesis in D2-mdx mice and implicates TGF-β as a major component of a pathogenic positive feedback loop in this model, identifying this feedback loop as a therapeutic target.

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.

The association of single nucleotide polymorphisms (SNPs) with breast density and breast cancer survival: the Malmö Diet and Cancer Study.

BackgroundGenetic factors are important in determining breast density, and heritable factors account for 60% of the variation. Certain single nucleotide polymorphisms (SNPs) are associated with density and risk of breast cancer but the association with prognosis is not clear.PurposeTo investigate associations between selected SNPs and breast cancer survival in the Malmö Diet and Cancer Study (MDCS).Material and MethodsA total of 724 unrelated women with breast cancer and registered radiological and pathological data were identified in MDCS 1991–2007, with genotyping available for 672 women. Associations among 15 SNPs, density, and breast cancer-specific survival were analyzed using logistic/Cox regression, adjusted for factors affecting density and survival. Variants significantly associated with either density or survival were validated in a large independent breast cancer cohort (LIBRO-1).ResultsMinor homozygotes of SNPs rs9383589, CCDC170 and rs6557161, ESR1 were associated with high breast density (adjusted odds ratio [AOR] 8.97, 95% confidence interval [CI] 1.35–59.57; AOR 2.08, 95% CI 1.19–3.65, respectively) and poorer breast cancer survival (adjusted hazard ratio [HRadj] 6.46, 95% CI 1.95–21.39; HRadj 2.30, 95% CI 1.33–3.96, respectively) compared to major homozygotes. For SNP rs3757318, ESR1, minor homozygotes (HRadj 7.46, 95% CI 2.28–24.45) were associated with poorer survival. We confirmed that rs6557161, ESR1 was significantly associated with both density and survival in the LIBRO-1 study.ConclusionThese findings support a shared genetic basis for density and breast cancer survival. The SNP significantly associated with both density and survival in both cohorts may be of interest in future research investigating polygenic risk scores for breast cancer risk and screening stratification purposes.

Genetic Heritability of Pigmentary Glaucoma and Associations With Other Eye Phenotypes

Mechanisms behind pigmentary glaucoma, a form of early-onset glaucoma that may potentially lead to severe visual impairment or blindness, are poorly understood. To calculate the single-nucleotide polymorphism (SNP) heritability of pigmentary glaucoma and identify genetic associations with the disease. This genome-wide association study included affected individuals from Germany and control participants from the United Kingdom. Genome-wide information was obtained for patients with pigmentary glaucoma and control participants free of glaucoma by using the Illumina Human Omni Express Exome 8v1-2 chip and genomic imputation. The SNP heritability of pigmentary glaucoma was estimated through a restricted maximum likelihood analysis. Associations between the genetic variants and pigmentary glaucoma obtained from age, sex, and principal component-adjusted logistic regression models were compared with those of SNPs previously associated with other eye phenotypes using Pearson product-moment correlations. Data were collected from November 2008 to January 2018, and analysis was completed between April 2018 and August 2019. An estimate of SNP-explained heritability for pigmentary glaucoma; correlations of effect sizes between pigmentary glaucoma and iris pigmentation and myopia; and correlations of effect sizes between pigmentary glaucoma and other eye phenotypes. A total of 227 affected individuals (mean [SD] age, 58.7 [13.3] years) and 291 control participants (mean [SD] age, 80.2 [4.9] years) were included; all were of European ancestry. The SNP heritability of pigmentary glaucoma was 0.45 (SE, 0.22; P = 6.15 × 10-10). Twelve SNPs previously reported with genome-wide significant associations with eye pigmentation were associated with pigmentary glaucoma's SNP heritability (4.9% SNP heritability; 0.022; P = 6.0 × 10-4). Pigmentary glaucoma SNP effect sizes were correlated moderately for myopia (r, 0.42 [95% CI, 0.14-0.63]; P = 4.3 × 10-3) and more strongly with those for iris pigmentation (r = -0.69 [95% CI, -0.91 to -0.20]; P = .01), although this was nonsignificant per a strict adjusted significance threshold (P < .01). These findings support the conclusion that pigmentary glaucoma may have a genetic basis and be highly heritable. Variants associated with lighter eye color and myopia appear to be associated with increased risk of pigmentary glaucoma, but no shared genetic basis with primary open-angle glaucoma (or its quantitative endophenotype of cup-disc ratio) was observed.

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10−8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10−12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21–1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01–1.35) and lung cancer in never smokers (OR = 1.56, 1.05–2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

A shared genetic basis of mimicry across swallowtail butterflies points to ancestral co-option of doublesex

Uncovering whether convergent adaptations share a genetic basis is consequential for understanding the evolution of phenotypic diversity. This information can help us understand the extent to which shared ancestry or independent evolution shape adaptive phenotypes. In this study, we first ask whether the same genes underlie polymorphic mimicry in Papilio swallowtail butterflies. By comparing signatures of genetic variation between polymorphic and monomorphic species, we then investigate how ancestral variation, hybridization, and independent evolution contributed to wing pattern diversity in this group. We report that a single gene, doublesex (dsx), controls mimicry across multiple taxa, but with species-specific patterns of genetic differentiation and linkage disequilibrium. In contrast to widespread examples of phenotypic evolution driven by introgression, our analyses reveal distinct mimicry alleles. We conclude that mimicry evolution in this group was likely facilitated by ancestral polymorphism resulting from early co-option of dsx as a mimicry locus, and that evolutionary turnover of dsx alleles may underlie the wing pattern diversity of extant polymorphic and monomorphic lineages.

Step changes in evolution

Summary Lineages changing their mode of locomotion are among the most conspicuous manifestations of evolutionary change. The appearance and disappearance of legs in events like the transition from fish to tetrapods, lizards to snakes, and tetrapods to whales has long fascinated biologists and lay people alike. Now genetics, developmental biology and paleontology are converging on a better understanding of these crucial transitions. Michael Gross reports.

Examination of the shared genetic basis of anorexia nervosa and obsessive–compulsive disorder

Examination of the shared genetic basis of anorexia nervosa and obsessive–compulsive disorder

Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder.

Disturbed sleep and activity are prominent features of bipolar disorder type I (BP-I). However, the relationship of sleep and activity characteristics to brain structure and behavior in euthymic BP-I patients and their non-BP-I relatives is unknown. Additionally, underlying genetic relationships between these traits have not been investigated. Relationships between sleep and activity phenotypes, assessed using actigraphy, with structural neuroimaging (brain) and cognitive and temperament (behavior) phenotypes were investigated in 558 euthymic individuals from multi-generational pedigrees including at least one member with BP-I. Genetic correlations between actigraphy-brain and actigraphy-behavior associations were assessed, and bivariate linkage analysis was conducted for trait pairs with evidence of shared genetic influences. More physical activity and longer awake time were significantly associated with increased brain volumes and cortical thickness, better performance on neurocognitive measures of long-term memory and executive function, and less extreme scores on measures of temperament (impulsivity, cyclothymia). These associations did not differ between BP-I patients and their non-BP-I relatives. For nine activity-brain or activity-behavior pairs there was evidence for shared genetic influence (genetic correlations); of these pairs, a suggestive bivariate quantitative trait locus on chromosome 7 for wake duration and verbal working memory was identified. Our findings indicate that increased physical activity and more adequate sleep are associated with increased brain size, better cognitive function and more stable temperament in BP-I patients and their non-BP-I relatives. Additionally, we found evidence for pleiotropy of several actigraphy-behavior and actigraphy-brain phenotypes, suggesting a shared genetic basis for these traits.