Teemu Palviainen

Objective: Polygenic risk scores (PRS) estimate genetically predicted BMI, but lifestyle and environmental factors may cause deviations between observed and predicted BMI. We investigated whether such deviations are associated with distinct molecular profiles and whether these differ by direction of deviation. Methods: We analyzed 2,508 adults from the Finnish Twin Cohort and 1,715 from the Young Finns Study with clinical, metabolomic, DNA methylation, and proteomic data. PRS-informed residual BMI (rBMI) quantified deviations between observed and genetically predicted BMI. Associations between rBMI and multi-omic profiles were assessed using linear mixed-effects models with a hinge term to compare effects above vs. below genetic prediction. Twin analyses further accounted for shared genetic and environmental factors. Results: rBMI is associated with distinct cardiometabolic and molecular profiles depending on whether BMI is above or below genetic prediction. When BMI exceeds genetic prediction, rBMI shows stronger associations with inflammatory and cardiovascular markers. In contrast, several metabolites and plasma proteins show stronger associations when BMI is below genetic prediction. Epigenetic aging increases with higher rBMI regardless of direction. Similar patterns are observed in BMI-discordant twin pairs. Conclusion: Deviations from genetically predicted BMI are associated with distinct clinical and molecular signatures beyond absolute BMI alone.

Social behaviour is a heritable trait linked to well-being and mental health, yet it varies across social context, including social domains, informants and development, which may shape its underlying genomic architecture. Here, we conducted a genome-wide meta-regression meta-analysis of social behaviour from infancy to early adulthood, studying ~500,000 repeated measures in European-ancestry cohorts ( N = 73,321). We modelled heterogeneity in single-variant associations across social domains (low prosocial behaviour and peer/social difficulties), multiple informants (parents, teachers and self-reports) and ages (2–29 years), identifying 6 associated loci, including variation within CADM2 ( P = 2.51 × 10 ⁻⁹ ). Single nucleotide polymorphism-based heritability ranged from 2% to 7%, and the genetic architecture comprised 4 factors reflecting differences in either social domains or informants. Polygenic scores ( N = 16,305) accurately predicted contextual variation in independent cohorts, with some cross-ancestry transferability. Context-specific patterns of genetic correlations, particularly when estimating the developmental onset of associations, offer opportunities to disentangle shared trajectories linking social behaviour with later-life and mental health outcomes.

Eating disorders—including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case–control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

Stressful life events (SLEs) are associated with increased risk of psychiatric and somatic disease, yet the molecular correlates of stress exposure across time remain incompletely characterised. We conducted a multi-omic analysis in the Finnish Twin Cohort, examining genomic ( n = 8,286), epigenomic ( n = 387), proteomic ( n = 401) and metabolomic ( n = 434) data across three exposure windows: recent (≤6 months), proximal (≤5 years) and lifetime. Genome-wide association analysis identified a single significant locus on chromosome 1 (lead SNP rs10158287, p = 9.7 × 10 ⁻⁹ ), mapping to DAB1 / C8B , with immune cell-specific eQTL effects in Th1/Th17 CD4 ⁺ T cells and cross-trait links to cardiometabolic risk; common variants explained 33.6% of variance in SLE scores; the DAB1 / C8B locus alone accounted for 0.4%, consistent with a highly polygenic architecture. No epigenome-wide significant associations or relationships with epigenetic ageing measures (PCPhenoAge, DunedinPACE, PCGrimAge) were detected. Circulating molecular layers showed temporally structured signatures. Recent SLEs were characterised by coordinated immune-metabolic changes, including five proteins (IL-1β, TIGIT, Nectin-1, Carnosinase-1, Calcyphosin; all decreased) and 16 metabolites predominantly reflecting reduced HDL-related lipids and broader lipid pools, alongside enrichment of the lipoprotein assembly and clearance pathway and lower thyroid and lung proteomic age estimates. Proximal exposure showed no significant single-analyte associations but convergent negative pathway-level signals involving cell-cycle and centrosome-associated processes. Lifetime SLEs were characterised by immune-vascular and tissue-remodelling signatures, including ten proteins (all increased), enrichment of TNF/IL-10 signalling, cellular maintenance and epithelial differentiation pathways, and higher arterial proteomic age. These findings indicate that molecular correlates of stress exposure are temporally contingent rather than uniformly accumulating across the life course, with convergent involvement of adaptive immune regulation alongside metabolic and vascular remodelling.

Tourette Syndrome and other tic disorders (TD) are common, highly heritable neurodevelopmental conditions with complex genetic architectures. We conducted a genome-wide association study of 13,247 TD cases and 536,217 European ancestry controls and identified six independent genome-wide significant loci, including a pleiotropic signal at 3p21 shared with attention-deficit/hyperactivity disorder, among other traits. Gene prioritization highlighted 20 genes, including PCDH9, HCN1, NCKIPSD, WDR6, DALRD3, and CELSR3. Integrative analyses provide genetic support for the role of cortico-striato-thalamo-cortical circuits in TD pathophysiology and further localize TD genetic risk to specific cell types, including dopamine D1- and D2-receptor-positive medium spiny neurons, cortical pyramidal neurons, and oligodendrocyte-lineage cells. We further demonstrate extensive genetic correlations with neurodevelopmental and psychiatric traits, but not with neurological disorders. These findings advance our understanding of the genetic basis of TD, pinpointing specific genes and cell types that drive pathophysiology and providing a foundation for future mechanistic studies.

Background: Previous studies have presented conflicting findings regarding the potential causal relationships between leisure-time physical activity (LTPA) and body mass index (BMI). Here, we use individual-level data and apply a triangulation framework that incorporates three complementary methods to investigate the bidirectional causal associations between LTPA and BMI. Methods: We used data from a longitudinal Finnish twin cohort with four measurement points spanning 36 years. The data included 22,696 twin individuals aged 18-50 years at baseline (52.4% women); 8,527 had genetic data available. We applied three analytical approaches suggested to strengthen causal inference in observational studies: Random intercept cross-lagged path model (RI-CLPM) for longitudinal data, one-sample Mendelian Randomization (MR) and Direction of Causation (DoC and MR-DoC) twin models for cross-sectional data at each measurement point. Results: All three approaches provided evidence for a causal effect of higher BMI on lower LTPA, particularly at the later follow-up stages. Only twin models suggested a negative causal effect of LTPA on BMI. Men and women showed mainly similar effects. Conclusions: Evidence triangulation across the three methodologies provided support for a causal effect of higher BMI on lower LTPA, whereas the evidence for a reverse effect was less convincing. Our results indicate that the role of high BMI in limiting LTPA becomes more important with advancing age, while also highlighting the importance of accounting for timing when studying the causal effects of LTPA on BMI and vice versa.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat–response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.