A study of the genetic architecture of social responsiveness in families with parental schizophrenia or bipolar disorder and population-based controls.

Twin-studies of social responsiveness have reported moderate to high heritabilities, but studies using parent-child data are lacking. Additionally, social impairments have been suggested as a vulnerability marker for schizophrenia and bipolar disorder, but the heritability of social responsiveness in this context is unknown. This study is part of the Danish High Risk and Resilience Study - VIA, comprising families with one parent with schizophrenia (n = 202) or bipolar disorder (n = 120) and population-based controls (PBC, n = 200). Social responsiveness was assessed with The Social Responsiveness Scale, Second Edition (SRS-2). Heritability was estimated from variance components, and a polygenic risk score (PRS) for autism spectrum disorder (ASD) was calculated to assess the genetic relationship between ASD and SRS-2. SRS-2 heritability was moderate to high and significantly different from zero in all groups when the children were rated by the primary caregiver. With teacher ratings, the heritability was lower and only significant in the full cohort and PBC. We found no significant association between SRS-2 and PRS for ASD. Our study confirms that social responsiveness is heritable, but that heritability estimates are affected by the child-respondent relation and familial risk of mental illness. This has implications for clinical practice and research using SRS-2 and provides insight on the familial transmission of mental illness.

Circulating S100B levels at birth and risk of six major neuropsychiatric or neurological disorders: a two-sample Mendelian Randomization Study.

Circulating levels of the astrocytic marker S100B have been associated with risk of neuropsychiatric or neurological disorders. However, reported effects have been inconsistent, and no causal relations have yet been established. We applied two-sample Mendelian Randomization (MR) on the association statistics from genome-wide association studies (GWAS) for circulating S100B levels measured 5-7 days after birth (the iPSYCH sample) and in an older adult sample (mean age, 72.5 years; the Lothian sample), upon those derived from major depression disorder (MDD), schizophrenia (SCZ), bipolar disorder (BIP), autism spectral disorder (ASD), Alzheimer's disease (AD), and Parkinson's disease (PD). We studied the causal relations in the two S100B datasets for risk of these six neuropsychiatric disorders. MR suggested increased S100B levels 5-7 days after birth to causally increase the risk of MDD (OR = 1.014; 95%CI = 1.007-1.022; FDR-corrected p = 6.43×10-4). In older adults, MR suggested increased S100B levels to have a causal relation to the risk of BIP (OR = 1.075; 95%CI = 1.026-1.127; FDR-corrected p = 1.35×10-2). No significant causal relations were found for the other five disorders. We did not observe any evidence for reverse causality of these neuropsychiatric or neurological disorders on altered S100B levels. Sensitivity analyses using more stringent SNP-selection criteria and three alternative MR models suggested the results are robust. Altogether, our findings imply a small cause-effect relation for the previously reported associations of S100B and mood disorders. Such findings may provide a novel avenue for the diagnosis and management of disorders.

Genetic and epidemiological analyses of infection load and its relationship with psychiatric disorders.

Severe infections and psychiatric disorders have a large impact on both society and the individual. Studies investigating these conditions and the links between them are therefore important. Most past studies have focused on binary phenotypes of particular infections or overall infection, thereby losing some information regarding susceptibility to infection as reflected in the number of specific infection types, or sites, which we term infection load. In this study we found that infection load was associated with increased risk for attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, schizophrenia and overall psychiatric diagnosis. We obtained a modest but significant heritability for infection load (h2 = 0.0221), and a high degree of genetic correlation between it and overall psychiatric diagnosis (rg = 0.4298). We also found evidence supporting a genetic causality for overall infection on overall psychiatric diagnosis. Our genome-wide association study for infection load identified 138 suggestive associations. Our study provides further evidence for genetic links between susceptibility to infection and psychiatric disorders, and suggests that a higher infection load may have a cumulative association with psychiatric disorders, beyond what has been described for individual infections.

Developmental language disorder - a comprehensive study of more than 46,000 individuals.

Developmental language disorder (DLD) is characterized by enduring low language abilities with a significant functional impact, in the absence of biomedical conditions in which language impairment is part of a complex of impairments. There is a lack of awareness of DLD even among healthcare professionals. Here we estimated the prevalence of DLD and its links to reading and learning difficulties and physical and mental health in the Danish Blood Donor Study (N = 46,547), where DLD-related information is based on questionnaires (self-report). We compared the questionnaire-derived DLD status with the relevant language-related diagnoses from hospital registers. We also investigated the genetic architecture of DLD in a subset of the cohort (N = 18,380). DLD was significantly associated with reading and learning difficulties and poorer mental and physical health. DLD prevalence was 3.36%-3.70% based on questionnaires, compared with 0.04% in hospital registers. Our genetic analyses identified one genome-wide significant locus, but not a significant heritability estimate. Our study shows that DLD has health-related implications that may last into adulthood, and that DLD may be undiagnosed in general healthcare. Furthermore, DLD is likely more genetically heterogeneous than narrower developmental language phenotypes. Our results emphasize the need to raise awareness of DLD and consider criteria for molecular studies of DLD to reduce case heterogeneity.

An immunogenetic investigation of 30 autoimmune and autoinflammatory diseases and their links to psychiatric disorders in a nationwide sample.

Autoimmune and autoinflammatory diseases (AIIDs) involve a deficit in an individual's immune system function, whereby the immune reaction is directed against self-antigens. Many AIIDs have a strong genetic component, but they can also be triggered by environmental factors. AIIDs often have a highly negative impact on the individual's physical and mental wellbeing. Understanding the genetic underpinning of AIIDs is thus crucial both for diagnosis and for identifying individuals at high risk of an AIID and mental illness as a result thereof. The aim of the present study was to perform systematic statistical and genetic analyses to assess the role of human leukocyte antigen (HLA) alleles in 30 AIIDs and to study the links between AIIDs and psychiatric disorders. We leveraged the Danish iPSYCH Consortium sample comprising 65 534 individuals diagnosed with psychiatric disorders or selected as part of a random population sample, for whom we also had genetic data and diagnoses of AIIDs. We employed regression analysis to examine comorbidities between AIIDs and psychiatric disorders and associations between AIIDs and HLA alleles across seven HLA genes. Our comorbidity analyses showed that overall AIID and five specific AIIDs were associated with having a psychiatric diagnosis. Our genetic analyses found 81 significant associations between HLA alleles and AIIDs. Lastly, we show connections across AIIDs, psychiatric disorders and infection susceptibility through network analysis of significant HLA associations in these disease classes. Combined, our results include both novel associations as well as replications of previously reported associations in a large sample, and highlight the genetic and epidemiological links between AIIDs and psychiatric disorders.

A family-based study of genetic and epigenetic effects across multiple neurocognitive, motor, social-cognitive and social-behavioral functions.

Many psychiatric and neurodevelopmental disorders are known to be heritable, but studies trying to elucidate the genetic architecture of such traits often lag behind studies of somatic traits and diseases. The reasons as to why relatively few genome-wide significant associations have been reported for such traits have to do with the sample sizes needed for the detection of small effects, the difficulty in defining and characterizing the phenotypes, partially due to overlaps in affected underlying domains (which is especially true for cognitive phenotypes), and the complex genetic architectures of the phenotypes, which are not wholly captured in traditional case-control GWAS designs. We aimed to tackle the last two issues by performing GWASs of eight quantitative neurocognitive, motor, social-cognitive and social-behavioral traits, which may be considered endophenotypes for a variety of psychiatric and neurodevelopmental conditions, and for which we employed models capturing both general genetic association and parent-of-origin effects, in a family-based sample comprising 402 children and their parents (mostly family trios). We identified 48 genome-wide significant associations across several traits, of which 3 also survived our strict study-wide quality criteria. We additionally performed a functional annotation of implicated genes, as most of the 48 associations were with variants within protein-coding genes. In total, our study highlighted associations with five genes (TGM3, CACNB4, ANKS1B, CSMD1 and SYNE1) associated with measures of working memory, processing speed and social behavior. Our results thus identify novel associations, including previously unreported parent-of-origin associations with relevant genes, and our top results illustrate new potential gene → endophenotype → disorder pathways.

Maternal pregnancy-related infections and autism spectrum disorder-the genetic perspective.

Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders which include deficits in behavior, social interaction and communication. ASD has a complex genetic architecture, and it is also influenced by certain environmental exposures. Both types of predisposing factors may be related to immunological mechanisms, involving, for example, immune system genes and infections. Past studies have shown an association between infections occurring during the pregnancy in the mother and increased risk of ASD in the child, an observation which has received recent support from experimental animal studies of ASD-like behavior. The aim of this study was to study the genetic contribution to this effect. We employed genetic correlation analyses across potential ASD subtypes stratified on the basis of maternal pregnancy-related infections within the iPSYCH ASD case-cohort sample, as well as a case-case GWAS. We validated the trends of the genetic correlation analyses observed in our sample using GWAS summary statistics from the PGC ASD study (excluding iPSYCH). The genetic correlation between ASD with a history of maternal pregnancy-related infections and ASD without a history of maternal infections in iPSYCH was rg = 0.3811. We obtained a similar estimate between the former and the PGC ASD phenotype (rg = 0.3997). Both estimates are lower compared to the genetic correlation between ASD without a history of maternal infections and the PGC ASD phenotype (rg = 0.6735), and between ASD with a history of maternal infections occurring only more than 2 months following childbirth and the PGC ASD phenotype (rg = 0.6293). Additionally, we observed genetic variance between the two main ASD phenotypes using summary statistics from the case-case GWAS in iPSYCH (h2cc = 0.1059), indicating genome-wide differences between the phenotypes. Our results suggest potentially different etiologies of ASD based on a history of maternal pregnancy-related infections, which may, in part, be genetic. This highlights the relevance of maternal pregnancy-related infections to genetic studies of ASD and provides new insights into the molecular underpinnings of ASD.

Genetic assortative mating for schizophrenia and bipolar disorder.

BACKGROUND: Psychiatric disorders are highly polygenic and show patterns of partner resemblance. Partner resemblance has direct population-level genetic implications if it is caused by assortative mating, but not if it is caused by convergence or social homogamy. Using genetics may help distinguish these different mechanisms. Here, we investigated whether partner resemblance for schizophrenia and bipolar disorder is influenced by assortative mating using polygenic risk scores (PRSs). METHODS: PRSs from The Danish High-Risk and Resilience Study-VIA 7 were compared between parents in three subsamples: population-based control parent pairs (N=198), parent pairs where at least one parent had schizophrenia (N=193), and parent pairs where at least one parent had bipolar disorder (N=115). RESULTS: The PRS for schizophrenia was predictive of schizophrenia in the full sample and showed a significant correlation between parent pairs (r=0.121, p=0.0440), indicative of assortative mating. The PRS for bipolar disorder was also correlated between parent pairs (r=0.162, p=0.0067), but it was not predictive of bipolar disorder in the full sample, limiting the interpretation. CONCLUSIONS: Our study provides genetic evidence for assortative mating for schizophrenia, with important implications for our understanding of the genetics of schizophrenia.

Deep learning-based integration of genetics with registry data for stratification of schizophrenia and depression.

Currently, psychiatric diagnoses are, in contrast to most other medical fields, based on subjective symptoms and observable signs and call for new and improved diagnostics to provide the most optimal care. On the basis of a deep learning approach, we performed unsupervised patient stratification of 19,636 patients with depression [major depressive disorder (MDD)] and/or schizophrenia (SCZ) and 22,467 population controls from the iPSYCH2012 case cohort. We integrated data of disorder severity, history of mental disorders and disease comorbidities, genetics, and medical birth data. From this, we stratified the individuals in six and seven unique clusters for MDD and SCZ, respectively. When censoring data until diagnosis, we could predict MDD clusters with areas under the curve (AUCs) of 0.54 to 0.80 and SCZ clusters with AUCs of 0.71 to 0.86. Overall cases and controls could be predicted with an AUC of 0.81, illustrating the utility of data-driven subgrouping in psychiatry.

The Danish High-Risk and Resilience Study-VIA 15 - A Study Protocol for the Third Clinical Assessment of a Cohort of 522 Children Born to Parents Diagnosed With Schizophrenia or Bipolar Disorder and Population-Based Controls.

Background: Children born to parents with severe mental illness have gained more attention during the last decades because of increasing evidence documenting that these children constitute a population with an increased risk of developing mental illness and other negative life outcomes. Because of high-quality research with cohorts of offspring with familial risk and increased knowledge about gene-environment interactions, early interventions and preventive strategies are now being developed all over the world. Adolescence is a period characterized by massive changes, both in terms of physical, neurologic, psychological, social, and behavioral aspects. It is also the period of life with the highest risk of experiencing onset of a mental disorder. Therefore, investigating the impact of various risk and resilience factors in adolescence is important. Methods: The Danish High-Risk and Resilience Study started data collection in 2012, where 522 7-year-old children were enrolled in the first wave of the study, the VIA 7 study. The cohort was identified through Danish registers based on diagnoses of the parents. A total of 202 children had a parent diagnosed with schizophrenia, 120 children had a parent diagnosed with bipolar disorder, and 200 children had parents without these diagnoses. At age 11 years, all children were assessed for the second time in the VIA 11 study, with a follow-up retention rate of 89%. A comprehensive assessment battery covering domains of psychopathology, neurocognition, social cognition and behavior, motor development and physical health, genetic analyses, attachment, stress, parental functioning, and home environment was carried out at each wave. Magnetic resonance imaging scans of the brain and electroencephalograms were included from age 11 years. This study protocol describes the third wave of assessment, the VIA 15 study, participants being 15 years of age and the full, 3-day-long assessment battery this time including also risk behavior, magnetoencephalography, sleep, and a white noise paradigm. Data collection started on May 1, 2021. Discussion: We will discuss the importance of longitudinal studies and cross-sectional data collection and how studies like this may inform us about unmet needs and windows of opportunity for future preventive interventions, early illness identification, and treatment in the future.

Infection Polygenic Factors Account for a Small Proportion of the Relationship Between Infections and Mental Disorders.

BACKGROUND: Several recent studies have suggested a role for infections in the development of mental disorders; however, the genetic contribution to this association is understudied. METHODS: We use the iPSYCH case-cohort genotyped sample (n = 65,534) and Danish health care registry data to study the genetic association between infections and mental disorders. To test the hypothesis that these associations are due to genetic pleiotropy, we estimated the genetic correlation between infection and mental disorders. Polygenic risk scores (PRSs) were used to assess whether genetic pleiotropy of infections and mental disorders was mediated by actual infection diagnoses. RESULTS: We observed that schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, and posttraumatic stress disorder (rg ranging between 0.18 and 0.83), but not autism spectrum disorder and anorexia nervosa, were significantly genetically correlated with infection diagnoses. PRSs for infections were associated with modest increase in risk of attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia in the iPSYCH case-cohort (hazard ratios = 1.04 to 1.10) but was not associated with risk of anorexia, autism, or bipolar disorder. Using mediation analysis, we show that infection diagnoses account for only a small proportion (6%-14%) of the risk for mental disorders conferred by infection PRSs. CONCLUSIONS: Infections and mental disorders share a modest genetic architecture. Infection PRSs can predict risk of certain mental disorders; however, this effect is moderate. Finally, recorded infections partially explain the relationship between infection PRSs and mental disorders.

Neurocognitive heterogeneity in 7-year-old children at familial high risk of schizophrenia or bipolar disorder: The Danish high risk and resilience study - VIA 7.

BACKGROUND: Studies of neurocognitive heterogeneity in young children at familial high-risk of bipolar disorder (FHR-BP) or schizophrenia (FHR-SZ) are important to investigate inter-individual neurocognitive differences. We aimed to identify neurocognitive subgroups, describe prevalence of FHR-BP or FHR-SZ children herein, and examine risk ratios (RR) compared with controls. METHODS: In a population-based cohort of 514 7-year-old children (197 FHR-SZ, 118 FHR-BP, and 199 matched controls) we used hierarchical cluster analyses to identify subgroups across 14 neurocognitive indices. RESULTS: Three neurocognitive subgroups were derived: A Mildly Impaired (30%), Typical (51%), and Above Average subgroup (19%). The Mildly Impaired subgroup significantly underperformed controls (Cohen d = 0.11-1.45; Ps < 0.001) except in set-shifting (P = .84). FHR-SZ children were significantly more prevalent in the Mildly Impaired subgroup; FHR-BP children were more so in the Above Average subgroup (X2 (2, N = 315) = 9.64, P < .01). 79.7% FHR-BP and 64.6% FHR-SZ children demonstrated typical or above average neurocognitive functions. Neurocognitive heterogeneity related significantly to concurrent functioning, psychopathology severity, home environment adequacy, and polygenic scores for schizophrenia (Ps <. 01). Compared with controls, FHR-SZ and FHR-BP children had a 93% (RR, 1.93; 95% CI, 1.40-2.64) and 8% (RR, 1.08; 95% CI, 0.71-1.66) increased risk of Mildly Impaired subgroup membership. LIMITATIONS: Limitations include the cross-sectional design and smaller FHR-BP sample size. CONCLUSIONS: Identification of neurocognitive heterogeneity in preadolescent children at FHR-BP or FHR-SZ may ease stigma and enable pre-emptive interventions to enhance neurocognitive functioning and resilience to mental illness in the impaired sub-population.

Pleiotropy between language impairment and broader behavioral disorders-an investigation of both common and rare genetic variants.

BACKGROUND: Language plays a major role in human behavior. For this reason, neurodevelopmental and psychiatric disorders in which linguistic ability is impaired could have a big impact on the individual's social interaction and general wellbeing. Such disorders tend to have a strong genetic component, but most past studies examined mostly the linguistic overlaps across these disorders; investigations into their genetic overlaps are limited. The aim of this study was to assess the potential genetic overlap between language impairment and broader behavioral disorders employing methods capturing both common and rare genetic variants. METHODS: We employ polygenic risk scores (PRS) trained on specific language impairment (SLI) to evaluate genetic overlap across several disorders in a large case-cohort sample comprising ~13,000 autism spectrum disorder (ASD) cases, including cases of childhood autism and Asperger's syndrome, ~15,000 attention deficit/hyperactivity disorder (ADHD) cases, ~3000 schizophrenia cases, and ~21,000 population controls. We also examine rare variants in SLI/language-related genes in a subset of the sample that was exome-sequenced using the SKAT-O method. RESULTS: We find that there is little evidence for genetic overlap between SLI and ADHD, schizophrenia, and ASD, the latter being in line with results of linguistic analyses in past studies. However, we observe a small, significant genetic overlap between SLI and childhood autism specifically, which we do not observe for SLI and Asperger's syndrome. Moreover, we observe that childhood autism cases have significantly higher SLI-trained PRS compared to Asperger's syndrome cases; these results correspond well to the linguistic profiles of both disorders. Our rare variant analyses provide suggestive evidence of association for specific genes with ASD, childhood autism, and schizophrenia. CONCLUSIONS: Our study provides, for the first time, to our knowledge, genetic evidence for ASD subtypes based on risk variants for language impairment.

A large-scale investigation into the role of classical HLA loci in multiple types of severe infections, with a focus on overlaps with autoimmune and mental disorders.

BACKGROUND: Infections are a major disease burden worldwide. While they are caused by external pathogens, host genetics also plays a part in susceptibility to infections. Past studies have reported diverse associations between human leukocyte antigen (HLA) alleles and infections, but many were limited by small sample sizes and/or focused on only one infection. METHODS: We performed an immunogenetic association study examining 13 categories of severe infection (bacterial, viral, central nervous system, gastrointestinal, genital, hepatitis, otitis, pregnancy-related, respiratory, sepsis, skin infection, urological and other infections), as well as a phenotype for having any infection, and seven classical HLA loci (HLA-A, B, C, DPB1, DQA1, DQB1 and DRB1). Additionally, we examined associations between infections and specific alleles highlighted in our previous studies of psychiatric disorders and autoimmune disease, as these conditions are known to be linked to infections. RESULTS: Associations between HLA loci and infections were generally not strong. Highlighted associations included associations between DQB1*0302 and DQB1*0604 and viral infections (P = 0.002835 and P = 0.014332, respectively), DQB1*0503 and sepsis (P = 0.006053), and DQA1*0301 with "other" infections (a category which includes infections not included in our main categories e.g. protozoan infections) (P = 0.000369). Some HLA alleles implicated in autoimmune diseases showed association with susceptibility to infections, but the latter associations were generally weaker, or with opposite trends (in the case of HLA-C alleles, but not with alleles of HLA class II genes). HLA alleles associated with psychiatric disorders did not show association with susceptibility to infections. CONCLUSIONS: Our results suggest that classical HLA alleles do not play a large role in the etiology of severe infections. The discordant association trends with autoimmune disease for some alleles could contribute to mechanistic theories of disease etiology.

Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders - Findings from a Danish population-based study.

BACKGROUND: Previous studies have indicated the bidirectionality between autoimmune and mental disorders. However, genetic studies underpinning the co-occurrence of the two disorders have been lacking. In this study, we examined the potential genetic contribution to the association between autoimmune and mental disorders and investigated the genetic basis of overall autoimmune disease. METHODS: We used diagnostic information from patients with seven autoimmune diseases and six mental disorders from the Danish population-based case-cohort sample (iPSYCH2012). We explored the epidemiological association using survival analysis and modelled the effect of polygenic risk scores (PRSs) on autoimmune and mental diseases. Genetic factors were investigated using GWAS and imputed HLA alleles in the iPSYCH cohort. RESULTS: Of 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two disease classes (P = 2.67 × 10-7, OR = 1.38, 95%CI = 1.22-1.56), with an overall bidirectional association, wherein individuals with autoimmune diseases had an increased risk of subsequent mental disorders (HR = 1.13, 95%CI: 1.07-1.21, P = 7.95 × 10-5) and vice versa (HR = 1.27, 95%CI = 1.16-1.39, P = 8.77 × 10-15). Adding PRSs to these adjustment models did not have an impact on the associations. PRSs for autoimmune diseases were only slightly associated with increased risk of mental disorders (HR = 1.01, 95%CI: 1.00-1.02, p = 0.038), whereas PRSs for mental disorders were not associated with autoimmune diseases overall. Our GWAS highlighted 12 loci on chromosome 6 (minimum P = 2.74 × 10-36, OR = 1.80, 95% CI: 1.64-1.96), which were implicated in gene regulation through bioinformatic functional analyses, thereby identifying new candidate genes for overall autoimmune disease. Moreover, we observed 20 human leukocyte antigen (HLA) alleles strongly associated, either positively or negatively, with overall autoimmune disease, but we did not find significant evidence of their associations with overall mental disorders. A GWAS of a comorbid diagnosis of an autoimmune disease and a mental disorder identified a genome-wide significant locus on chromosome 7 as well (P = 1.43 × 10-8, OR = 10.65, 95%CI = 3.21-35.36). CONCLUSIONS: Our findings confirm the overall comorbidity and bidirectionality between autoimmune diseases and mental disorders and identify HLA genes which are significantly associated with overall autoimmune disease. Additionally, we identified several new candidate genes for overall autoimmune disease and ranked them based on their association with the investigated diseases.

Genome-wide association study identifies 16 genomic regions associated with circulating cytokines at birth.

Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

Quantitative genome-wide association analyses of receptive language in the Danish High Risk and Resilience Study.

BACKGROUND: One of the most basic human traits is language. Linguistic ability, and disability, have been shown to have a strong genetic component in family and twin studies, but molecular genetic studies of language phenotypes are scarce, relative to studies of other cognitive traits and neurodevelopmental phenotypes. Moreover, most genetic studies examining such phenotypes do not incorporate parent-of-origin effects, which could account for some of the heritability of the investigated trait. We performed a genome-wide association study of receptive language, examining both child genetic effects and parent-of-origin effects. RESULTS: Using a family-based cohort with 400 children with receptive language scores, we found a genome-wide significant paternal parent-of-origin effect with a SNP, rs11787922, on chromosome 9q21.31, whereby the T allele reduced the mean receptive language score by ~ 23, constituting a reduction of more than 1.5 times the population SD (P = 1.04 × 10-8). We further confirmed that this association was not driven by broader neurodevelopmental diagnoses in the child or a family history of psychiatric diagnoses by incorporating covariates for the above and repeating the analysis. CONCLUSIONS: Our study reports a genome-wide significant association for receptive language skills; to our knowledge, this is the first documented genome-wide significant association for this phenotype. Furthermore, our study illustrates the importance of considering parent-of-origin effects in association studies, particularly in the case of cognitive or neurodevelopmental traits, in which parental genetic data are not always incorporated.