Publications

Polygenic scores (PGS) enable the exploration of pleiotropic effects and genomic dissection of complex traits. Here, in 421,889 individuals with European ancestry from the Million Veteran Program and UK Biobank, we examine how PGS of 17 neuropsychiatric traits are related to membership in 22 broad professional categories. Overall, we find statistically significant but weak (the highest odds ratio is 1.1 per PGS standard deviation) associations between most professional categories and genetic predisposition for at least one neuropsychiatric trait. Secondary analyses in UK Biobank revealed independence of these associations from observed fluid intelligence and sex-specific effects. By leveraging aggregate population trends, we identified patterns in the public interest, such as the mediating effect of education attainment on the association of attention-deficit/hyperactivity disorder PGS with multiple professional categories. However, at the individual level, PGS explained less than 0.5% of the variance of professional membership, and almost none after we adjusted for education and socio-economic status.

Until two decades ago, brown adipose tissue (BAT) was studied primarily as a thermogenic organ of small rodents in the context of cold adaptation. The discovery of functional human BAT has opened new opportunities to understand its physiological role in energy balance and therapeutic applications for metabolic disorders. Significantly, the role of BAT extends far beyond thermogenesis, including glucose and lipid homeostasis, by releasing mediators that communicate with other cells and organs. The field has made major advances by using new model systems, ranging from subcellular studies to clinical trials, which have also led to debates. In this perspective, we identify six fundamental issues that are currently controversial and comprise dichotomous models. Each side presents supporting evidence and, critically, the necessary methods and falsifiable experiments that would resolve the dispute. With this collaborative approach, the field will continue to productively advance the understanding of BAT physiology, appreciate the importance of thermogenic adipocytes as a central area of ongoing research, and realize the therapeutic potential.

Isocitrate dehydrogenase (IDH) mutants define a class of gliomas that are initially slow-growing but inevitably progress to fatal disease. To characterize their malignant cell hierarchy, we profiled chromatin accessibility and gene expression across single cells from low-grade and high-grade IDH-mutant gliomas and ascertained their developmental states through a comparison to normal brain cells. We provide evidence that these tumors are initially fueled by slow-cycling oligodendrocyte progenitor cell-like cells. During progression, a more proliferative neural progenitor cell-like population expands, potentially through partial reprogramming of 'permissive' chromatin in progenitors. This transition is accompanied by a switch from methylation-based drivers to genetic ones. In low-grade IDH-mutant tumors or organoids, DNA hypermethylation appears to suppress interferon (IFN) signaling, which is induced by IDH or DNA methyltransferase 1 inhibitors. High-grade tumors frequently lose this hypermethylation and instead acquire genetic alterations that disrupt IFN and other tumor-suppressive programs. Our findings explain how these slow-growing tumors may progress to lethal malignancies and have implications for therapies that target their epigenetic underpinnings.

Genome-wide association studies have revealed that the genetic architecture of most complex traits is characterized by a large number of distinct effects scattered across the genome. Functional enrichment analyses help provide some biological interpretation of associated variants but more work is needed to further translate GWAS hits into meaningful biological insights. Thus, we set out to leverage the genetic association results from many traits with a view to identifying the set of modules, or latent factors, that mediate these associations. The identification of such modules may aid in disease classification as well as the elucidation of complex disease mechanisms. We propose a method, Genetic Unmixing by Independent Decomposition (GUIDE), to estimate a set of statistically independent latent factors that best express the patterns of association across many traits. The resulting latent factors not only have desirable mathematical properties, such as sparsity and a higher variance explained for the latent factors that are significantly associated with a given trait, but are also able to single out and prioritize key biological features or pathophysiological mechanisms underlying a given trait or disease. Moreover, we show that these latent factors can isolate biological pathways as well as epidemiological and environmental influences that compose the genetic architecture of complex traits.

BACKGROUND: Relative risk estimates of familial aggregation of many types of mental disorders are available, but absolute risk estimates of familial aggregation of mental disorders remain sparse. The proportion of individuals who develop a mental disorder in the absence of the same disorder in a relative (non-familial cases) has not been examined. We aimed to create comprehensive risk estimates of the familial aggregation of mental disorders.

METHODS: In this prospective cohort study, we followed people of Danish origin between Jan 1, 1970, and Dec 31, 2021. We used Danish population-based registers to link individuals and their mental health across extended family pedigrees. These registers include the Danish Civil Registration System, the Danish Multi Generation Register, the Danish Psychiatric Central Research Register, and the Danish National Patient Register. Mental disorders investigated were substance use disorder, cannabis use disorder, alcohol use disorder, schizophrenia and related disorders, schizophrenia, schizoaffective disorder, mood disorders, bipolar disorder, single and recurrent depressive disorders (depression), personality disorder, borderline personality disorder, and antisocial personality disorder. We estimated lifetime risk (risk up to age 60 years), age-specific absolute risk, and relative risk for each mental disorder and type of affected relative (eg first, second, or third-degree relatives). We calculated heritability estimates and the proportion of non-familial cases. We involved people with related lived experience in the study design and implementation.

FINDINGS: A total of 3 048 583 individuals (1 486 132 [48·75%] females and 1 562 451 [51·25%] males) were followed up for 80 425 971 person-years. Individuals with a family member with a specific type of mental disorder had higher lifetime and relative risks of developing the same type of mental disorder. Both lifetime and relative risks were higher the closer the affected kinship. For example, the lifetime risk of depression was 15·48% (95% CI 15·31-15·65) in individuals with affected first-degree relatives, 13·50% (13·25-13·75) in individuals with affected second-degree relatives, 7·80% (7·76-7·84) in the general population, and 4·68% (4·65-4·71) in individuals without affected first-degree and second-degree relatives. The heritability for depression was 45·4% (95% CI 44·8-46·0) and the proportion of non-familial cases constituted 60·0% (95% CI 59·8-60·2).

INTERPRETATION: Individuals with family members with a mental disorder face increased risks of the same disorder. From a population perspective, most mental disorders occur in individuals without affected close relatives, thus highlighting the need for prevention strategies which target the entire population.

FUNDING: Novo Nordisk Foundation.

TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

BACKGROUND: Cancer predisposition syndromes (CPSs) with pediatric onset are the leading known cause of childhood malignancies and are increasingly guiding clinical strategies in pediatric oncology. CPSs are placed under evolutionary negative selective pressure, but pediatric pancancer studies have so far failed to investigate genomic evolutionary metrics as a guide to predict penetrance and reveal novel CPSs.

METHOD: Germline whole-genome sequencing (WGS) in a 5-year prospective, registry-validated, nationwide cohort of individuals diagnosed with cancer before 18 years of age. Evolution-guided burden analysis of private germline variants in constrained genes compared with 125,748 gnomAD exomes.

RESULTS: Across a total of 1,127 participants, 16% carried a pathogenic variant in at least one CPS gene. After genotype-phenotype matching, 9 % of children in the prospective cohort (n=651) carried a variant considered causative, a rate deemed significantly higher than previous studies (RR=1.54,95%CI1.37-1.75,p=1e-14). As predicted for a disease subject to negative Darwinian selective pressure, compared to reference adults, we found a significant excess of loss-of-function (LoF) variants in the 1,500 most constrained genes (RR=1.54,99%CI 1.21-1.95,p=4e-6). Surprisingly, this excess was greater than expected, leaving a significant residual enrichment of pLoF variants in genes evolutionarily considered the least tolerant to damage (RR=1.41,99%CI1.09-1.80,p=4e-4).

CONCLUSION: The high frequency of LoF variants, including in known CPSs, emphasizes the need for systematic and extensive germline genomic mapping as part of the diagnostic work-up of childhood cancer patients and linkage of such data to disease and response phenotypes to guide future pediatric oncological care, and ultimately paving the way for pre-diagnostic interventional measures.

BACKGROUND: Previous research has shown that females who use hormonal contraception are at increased risk of developing depression, and that the risk is highest among adolescents. While this finding could reflect age-specific effects of exogenous hormones on mental health, genetic liability for mental disorders could be confounding the association. Our goal was to test the plausibility of this hypothesis by determining whether polygenic liabilities for major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SCZ), and attention deficit hyperactivity disorder (ADHD) are associated with younger age at hormonal contraception initiation.

METHODS: We conducted a cohort study using data from the Danish iPSYCH2015 sub-cohort, a representative sample of people born in Denmark between May 1981 and December 2008. Polygenic scores (PGSs) for MDD, BD, SCZ, and ADHD were created using the most recent genome-wide association study meta-analyses from the Psychiatric Genomics Consortium. Associations between PGSs and hormonal contraception initiation in the following age categories: 10-14, 15-19, 20-24, and 25+ were examined via Cox regression. We examined any hormonal contraception, oral contraception, and non-oral contraception.

RESULTS: PGS-MDD and PGS-ADHD showed the strongest associations with hormonal contraception initiation at age 10-14 (PGS-ADHD: HR = 1.21 [95% CI = 1.16-1.27], p = 6.16 x 10-18; PGS-MDD: 1.21 [1.16-1.27], p = 1.22 x 10-17). The associations then steadily decreased as age at hormonal contraception initiation increased. Both PGS-MDD and PGS-ADHD were also associated with initiation at ages 15-19, but not at 20-24 or 25+. PGS-BD and PGS-SCZ were also associated, albeit not as strongly, with initiation at age 10-14 only (PGS-BD: 1.07 [1.02-1.13], p = 6.87 × 10-3; PGS-SCZ: 1.09 [1.04-1.14], p = 8.61 × 10-4).

CONCLUSIONS AND RELEVANCE: These results suggest that genetic confounding could explain some of the association between early hormonal contraception use and depression. Where possible, researchers studying this important topic should account for possible confounding by genetic liability for mental disorders.

BACKGROUND: There is growing evidence linking neonatal vitamin D deficiency to an increased risk of schizophrenia, ADHD, and autism spectrum disorder (ASD). The aim of this study was to examine the association between two vitamin D biomarkers (25 hydroxyvitamin D [25(OH)D] and vitamin D-binding protein [DBP], and their related genetic correlates) and the risk of six mental disorders.

METHODS: We used a population-based, case-cohort sample of all individuals born in Denmark between 1981 and 2005. Using Danish health registers with follow-up to Dec 31, 2012, we identified individuals diagnosed with major depressive disorder, bipolar disorder, schizophrenia, ADHD, ASD, and anorexia nervosa based on ICD-10 criteria. Additionally, a random subcohort from the general population was selected. Based on neonatal dried blood spots, we measured concentrations of 25(OH)D and DBP. Our primary analyses were based on hazard ratios (HR) with 95% CI and absolute risks for the six mental disorders according to measured concentrations of 25(OH)D and DBP. As secondary analyses, we examined the association between genetic predictors of 25(OH)D and DBP, and the six mental disorders, and Mendelian randomisation analyses based on published summary statistics for 25(OH)D, DBP, and the six mental disorders. People with lived experience contributed to the development of the guiding hypothesis.

FINDINGS: We used the total population from the iPSYCH2012 design (n=88 764), which included individuals who developed the six mental disorders, major depressive disorder (n=24 240), bipolar disorder (n=1928), schizophrenia (n=3540), ADHD (n=18 726), ASD (n=16 146), anorexia nervosa (n=3643), and the randomly sampled subcohort (n=30 000). Among those who met a range of inclusion criteria (eg, measured 25[OH]D, DBP or genotype, and predominantly European ancestry), we measured 25(OH)D or DBP in 71 793 individuals (38 118 [53·1%] male and 33 675 [46·9%] female); 65 952 had 25(OH)D and 66 797 the DBP measurements. Significant inverse relationships were found between 25(OH)D and schizophrenia (HR 0·82, 95% CI 0·78-0·86), ASD (HR 0·93, 95% CI 0·90-0·96), and ADHD (HR 0·89, 95% CI 0·86-0·92). A significant inverse relationship was found between DBP and schizophrenia (HR 0·84, 95% CI 0·80-0·88). Based on polygenic risk scores, higher concentrations of 25(OH)D (adjusted for DBP) were significantly associated with a reduced risk of both ASD and schizophrenia. Analyses based on Mendelian randomisation provided support for a causal association between both lower 25(OH)D and DBP concentrations and an increased risk of ADHD.

INTERPRETATION: Convergent evidence finds that neonatal vitamin D status is associated with an altered risk of mental disorders. Our study supports the hypothesis that optimising neonatal vitamin D status might reduce the incidence of a range of neurodevelopmental disorders.

FUNDING: The Danish National Research Foundation.

BACKGROUND: Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. We investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort.

METHODS: The sample comprised 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) and with at least two registered hospital contacts between 1995 and 2018. Based on medical records, the occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGSs and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models.

RESULTS: A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Rates of presumed remission ranged between 86.9% and 89.8%. Higher (1 SD increase) PGSs for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGSs for a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Having a higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for overall health rating showed the opposite.

CONCLUSIONS: We found that most patients with an ED did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have a significant polygenic component.