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The spatial distribution of cell surface proteins governs vital processes of the immune system such as intercellular communication and mobility. However, fluorescence microscopy has limited scalability in the multiplexing and throughput needed to drive spatial proteomics discoveries at subcellular level. We present Molecular Pixelation (MPX), an optics-free, DNA sequence-based method for spatial proteomics of single cells using antibody–oligonucleotide conjugates (AOCs) and DNA-based, nanometer-sized molecular pixels. The relative locations of AOCs are inferred by sequentially associating them into local neighborhoods using the sequence-unique DNA pixels, forming >1,000 spatially connected zones per cell in 3D. For each single cell, DNA-sequencing reads are computationally arranged into spatial proteomics networks for 76 proteins. By studying immune cell dynamics using spatial statistics on graph representations of the data, we identify known and new patterns of spatial organization of proteins on chemokine-stimulated T cells, highlighting the potential of MPX in defining cell states by the spatial arrangement of proteins.

Psychiatric comorbidity can be accounted for by a latent general psychopathology factor (p factor), which quantifies the variance that is shared to varying degrees by every dimension of psychopathology. It is unclear whether the entire continuum of the p factor shares the same genetic origin. We investigated whether mild, moderate, and extreme elevations on the p factor shared the same genetic etiology by, first, examining the linearity of the association between p factors across siblings (N= 580,891 pairs). Second, we estimated the group heritability in a twin sample (N= 17,170 pairs), which involves testing whether the same genetic variants influence both extreme and normal variations in the p factor. In both samples, the p factor was based on 10 register-based psychiatric diagnoses. Results showed that the association between siblings’ p factors appeared linear, even into the extreme range. Likewise, the twin group heritabilities ranged from 0.42 to 0.45 (95% CI: 0.33–0.57) depending on the thresholds defining the probands (2–3.33 SD beyond the mean; >2 SD beyond the mean; >4.33 SD beyond the mean; and >5.33 SD beyond the mean), and these estimates were highly similar to the estimated individual differences heritability (0.41, 95% CI: 0.39–0.43), indicating that scores above and below these thresholds shared a common genetic origin. Together, these results suggest that the entire continuum of the p factor shares the same genetic origin, with common genetic variants likely playing an important role. This implies, first, genetic risk factors for the aspect that is shared between all forms of psychopathology (i.e., genetic risk factors for the p factor) might be generalizable between population-based cohorts with a higher prevalence of milder cases, and clinical samples with a preponderance of more severe cases. Second, prioritizing low-cost genome-wide association studies capable of identifying common genetic variants, rather than expensive whole genome sequencing that can identify rare variants, may increase the efficiency when studying the genetic architecture of the p factor.

Many studies document the relationship between child maltreatment (CM) and increased risk of chronic pain. However, estimating the effect of CM on chronic pain is challenging given the threat of familial and other environmental confounding. We used a co-twin control approach to examine the potential causal relationship between self-reported CM (i.e., experiencing any emotional, physical, or sexual abuse, physical neglect, or witnessing family violence) and self-reported chronic widespread pain (CWP) symptom counts after ruling out familial confounding by design. We applied a complete case approach to cross-sectional, national Swedish data from the Study of Twin Adults: Genes and Environment (N= 6,936 individuals in complete twin pairs; Mage= 32.9; SDage= 7.7; 60.5% female). Negative binomial generalized estimating equation models examined unrelated-individual and within-twin-pair associations between CM and CWP. Adjusting for age and biological sex, CM was associated with increased rates of CWP symptoms among unrelated individuals (incidence rate ratio [IRR], 2.35 [95% CI: 2.02, 2.74]). In the within-twin-pair comparison, which provided a stronger test of a causal effect independent of familial confounding, the association attenuated only slightly (IRR, 1.74 [1.36, 2.22]). That is, twins who experienced CM were expected to have relatively greater CWP symptoms than their co-twins who did not experience CM. Restricting the sample to monozygotic twins to further rule out genetic confounding produced similar results (IRR, 1.87 [1.29, 2.70]). Findings preliminarily support the hypothesis that CM is an important risk factor of CWP. Future directions include statistically accounting for missing data to further examine causality.

Chronic overlapping pain conditions (COPCs) by definition frequently co-occur, perhaps reflecting their shared etiologies. Their overlapping nature presents a methodological challenge, possibly masking associations between COPCs and health outcomes attributable to either general or specific processes. To address this challenge, we used population-based cohort data to evaluate the predictive validity of a bifactor model of nine self-reported COPCs by assessing its association with incident pain-related clinical diagnoses; pain-relevant pharmacotherapy; and other health outcomes. We obtained data from a 2005-2006 study of Swedish adult twins linked with health data from nationwide registers through 2016 (N= 25,418). We then fit a bifactor model comprising a general COPC factor and two independent specific factors measuring pain-related somatic symptoms and neck and shoulder pain. Accounting for age, biological sex, and cancer, the general factor was associated with increased risk of all pain-related outcomes (e.g., COPC diagnosis aOR, 1.71; 95% CI [1.62, 1.81]), most mental health-related outcomes (e.g., depression aOR, 1.72 [1.60, 1.85]), and overdose and mortality (e.g., all-cause mortality aOR, 1.25 [1.09, 1.43]). The somatic symptoms specific factor was associated with pain-relevant pharmacotherapy (e.g., prescribed opioids aOR, 1.25 [1.15, 1.36]), most mental health-related outcomes (e.g., depression aOR, 1.95 [1.70, 2.23]), and overdose (e.g., nonfatal overdose aOR, 1.66 [1.31, 2.10]). The neck and shoulder pain specific factor was weakly and inconsistently associated with the outcomes. Findings provide initial support for the validity and utility of a general-factor model of COPCs as a tool to strengthen understandings of co-occurrence, etiology, and consequences of chronic pain.

Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R2= 0.26–1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09–0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (pvalue < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (pvalue < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

In recent years, there has been a surge of interest in the general factor of psychopathology (“p”), which is intended to summarize broad psychiat­ric comorbidity into a single index. In this study, rather than attempting to validate this model using statistical techniques, we compared the magnitude (as indicated by the variance explained in the respective indicators) and the predictive validity of the “p” factor with those of the gen­eral factor of intelligence (“g”). To compare the magnitude, for “g”, we analyzed fifteen Wechsler Adult Intelligence Scale subtests (N=1,200). For “p”, we analyzed fourteen psychiatric diagnoses in Swedish adults (N=909,699), eight self‐ and parent‐rated psychopathology scales in Swedish adolescents (N=2,069), and sixteen parent‐rated psychopathology scales in Swedish children (N=14,589). To compare the predictive validity, we analyzed Swedish male military conscripts (N=414,595, mean age: 18.3 years) with measures on both “g” and “p” (derived from eight psychiatric diagnoses). We then examined their unique associations with three intelligence‐related outcomes (annual income, highest education, and university entrance exam scores), and sixteen adverse outcomes (e.g., suicidal behavior, psychotropic medication prescription, and criminality) retrieved from registers (mean age at follow‐up = 29.2 years). Results indicated that the magnitudes of “g” and “p” were very similar. Controlling for “p”, “g” significantly predicted later education (standardized beta, β=0.38, SE=0.01) and university entrance exam scores (β=0.48, SE=0.01). Controlling for “g”, “p” significantly predicted all adverse outcomes (mean β=0.32; range: 0.15 to 0.47). These findings support the notion that psychopathology indicators can be combined into a single score, similar to how intelligence subtests are combined into a general intelligence score. This “p” score might supplement specific diagnoses when formulating a management plan and predicting prognosis.

Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure.

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype. A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent risk loci. Comparisons with other psychiatric disorders and candidate gene analyses provide new insights into major depressive disorder.

Children with attention‐deficit/hyperactivity disorder (ADHD) are at increased risk of problematic alcohol and other substance use in adolescence. This study used data from an ongoing, prospective, population‐based twin study of Swedish children and adolescents to evaluate the extent to which the association between ADHD symptoms and alcohol problems reflects a unique source of genetic or environmental risk related to ADHD versus a broader predisposition to youth externalizing behavior. We used all available data from same‐sex monozygotic (MZ) and dizygotic (DZ) twins on ADHD symptoms in childhood (age 9/12; N = 15,549) and alcohol problems in late adolescence (age 18; N = 2,564). Consistent with prior longitudinal studies, the phenotypic association between hyperactive/impulsive ADHD symptoms and alcohol problems was small in magnitude, whereas the association for inattentive symptoms was even weaker. Additive genetic influences explained 99.8% of the association between hyperactive/impulsive symptoms and alcohol problems. Furthermore, we found that the genetic risk specifically associated with hyperactive/impulsive symptoms was attenuated when estimated in the context of externalizing behavior liability during childhood, of which ADHD symptoms were specific expressions. In sensitivity analyses exploring hyperactivity in mid‐adolescence, we found a similar pattern of genetic associations. These results are consistent with previous findings of genetically driven overlap in the etiology of ADHD and problematic alcohol use. At least some of this co‐occurrence may result from a general predisposition to externalizing behaviors in youth. © 2015 Wiley Periodicals, Inc.

Studies suggest associations between childhood autistic traits and adolescent psychotic experiences. However, recent research suggests that a general neuropsychiatric problems factor predicts adverse outcomes better than specific diagnostic entities. To examine if the alleged association between autistic traits and psychotic experiences could rather be explained by a general neuropsychiatric problems factor comprising symptoms of ADHD, tic disorder, developmental coordination disorder, and learning disorder, we conducted a prospective cohort study based on the Child and Adolescent Twin Study in Sweden. In addition, we examined the genetic and environmental influences on the associations. A total of 9,282 twins with data on childhood autistic traits and other neuropsychiatric problems, and follow‐up data on psychotic experiences at ages 15 and/or 18 years were included. First, psychotic experiences were regressed on autistic traits and second, the general neuropsychiatric problems factor was added to the model. Auditory hallucinations were analyzed separately from the other psychotic experiences. Finally, twin analyses were employed to disentangle genetic from environmental influences in the observed associations. Replicating prior research, significant associations were found between autistic traits in childhood and auditory hallucinations at ages 15 and 18. However, after controlling for the general neuropsychiatric problems factor, the associations between autistic traits and auditory hallucinations disappeared, whereas the association between the general neuropsychiatric problems factor and auditory hallucinations persisted after controlling for autistic traits. Twin analyses revealed that the association between the general neuropsychiatric problems factor and auditory hallucinations was driven by shared genetic influences. © 2015 Wiley Periodicals, Inc.

Understanding the dynamics of the human proteome is crucial for developing biomarkers to be used as measurable indicators for disease severity and progression, patient stratification, and drug development. The Proximity Extension Assay (PEA) is a technology that translates protein information into actionable knowledge by linking protein-specific antibodies to DNA-encoded tags. In this report we demonstrate how we have combined the unique PEA technology with an innovative and automated sample preparation and high-throughput sequencing readout enabling parallel measurement of nearly 1500 proteins in 96 samples generating close to 150,000 data points per run. This advancement will have a major impact on the discovery of new biomarkers for disease prediction and prognosis and contribute to the development of the rapidly evolving fields of wellness monitoring and precision medicine.

We examined longitudinal associations of resting heart rate (RHR) and general intelligence (IQ) with two psychopathology models (correlated factors and general factor model). RHR and IQ were measured during conscription (mean age = 18.23 years; N= 899,398 Swedish males). A correlated factors model of register-based outcomes (including 10 psychiatric diagnoses, criminal convictions, and prescription of anxiolytic medications; mean age at follow-up = 43.09 years) identified internalizing, externalizing, and psychotic dimensions; the general factor model additionally identified a general dimension. All correlated factors were inversely associated with IQ; however, the general factor model showed that several of these associations were attributable to general variance rather than specific variance. In both psychopathology models, RHR weakly but significantly predicted higher internalizing but lower externalizing problems. Intelligence might be a transdiagnostic risk factor for any form of psychopathology, and the internalizing and externalizing spectra might be differentiated by psychobiological processes related to sensitivity to punishment.

The cover image, by Patrick D. Quinn, et al., is based on the Research Article Childhood Attention‐Deficit/Hyperactivity Disorder Symptoms and the Development of Adolescent Alcohol Problems: A Prospective, Population‐Based Study of Swedish Twins, DOI: 10.1002/ajmg.b.32412.