Andrew McQuillin

BackgroundThe study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex.ResultsWe found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific …

Lithium is a first-line treatment option for bipolar disorder (BD). However, the response to treatment is variable, and lithium is associated with significant side-effects. Efforts to examine the influence of genetics in the efficacy of lithium using genome-wide association studies (GWAS) have identified several loci. We report data from 1259 participants with BD recruited at University College London who had been treated with lithium. The data comes from three waves of genotyping on different arrays. The GWAS data from each array was analysed separately and then meta-analysed with two published lithium response GWAS datasets. Post-GWAS analyses were conducted to examine the heritability of lithium response and genetic correlations with other traits. We also attempted to replicate past polygenic risk scores (PRS) results. SNP rs116927879 (A/G) was associated with good lithium response at a genome-wide level of significance (p= 4.509× 10− 08) with a consistent effect across all cohorts. rs116927879 is located on chromosome 7 and maps to the protein coding gene ADCY1 and two pseudo-genes, GTF2IP13 and SEPT7P2. ADCY1 plays a role in the regulatory processes in the central nervous system, memory, and learning. We estimated the SNP heritability (h 2) for good lithium response as 20.3% and 15.6% for subjective and objective response definitions, respectively. We did not observe any genetic correlation or PRS association between the lithium response and schizophrenia or major depression disorder. However, we found weak evidence to suggest that males were more likely to be good responders. Our GWAS identifies a genome …

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic …

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Background Increased rates of visual impairment are observed in people with schizophrenia. Aims We assessed whether genetically predicted poor distance acuity is causally associated with schizophrenia, and whether genetically predicted schizophrenia is causally associated with poorer visual acuity. Method We used bidirectional, two-sample Mendelian randomisation to assess the effect of poor distance acuity on schizophrenia risk, poorer visual acuity on schizophrenia risk and schizophrenia on visual acuity, in European and East Asian ancestry samples ranging from approximately 14 000 to 500 000 participants. Genetic instrumental variables were obtained from the largest available summary statistics: for schizophrenia, from the Psychiatric Genomics Consortium; for visual acuity, from the UK Biobank; and for poor distance acuity, from a meta-analysis of case–control samples. We used the inverse …

AimWe investigated the predictive value of polygenic risk scores (PRS) derived from the schizophrenia GWAS (Trubetskoy et al., 2022) (SCZ3) for phenotypic traits of bipolar disorder type-I (BP-I) in 1878 BP-I cases and 2751 controls from Romania and UK.MethodsWe used PRSice-v2.3.3 and PRS-CS for computing SCZ3-PRS for testing the predictive power of SCZ3-PRS alone and in combination with clinical variables for several BP-I subphenotypes and for pathway analysis. Non-linear predictive models were also used.ResultsSCZ3-PRS significantly predicted psychosis, incongruent and congruent psychosis, general age-of-onset (AO) of BP-I, AO-depression, AO-Mania, rapid cycling in univariate regressions. A negative correlation between the number of depressive episodes and psychosis, mainly incongruent and an inverse relationship between increased SCZ3-SNP loading and BP-I-rapid cycling were …

BackgroundThe N100, an early auditory event-related potential, has been found to be altered in patients with psychosis. However, it is unclear if the N100 is a psychosis endophenotype that is also altered in the relatives of patients.MethodsWe conducted a family study using the auditory oddball paradigm to compare the N100 amplitude and latency across 243 patients with psychosis, 86 unaffected relatives, and 194 controls. We then conducted a systematic review and a random-effects meta-analysis pooling our results and 14 previously published family studies. We compared data from a total of 999 patients, 1192 relatives, and 1253 controls in order to investigate the evidence and degree of N100 differences.ResultsIn our family study, patients showed reduced N100 amplitudes and prolonged N100 latencies compared to controls, but no significant differences were found between unaffected relatives and …

BackgroundConsumption of nicotine, alcohol, and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability to substance involvement.MethodsTo elucidate its genetic architecture, we modeled a common liability inferred from genetic correlations among 6 measures of dependence and frequency of use of nicotine, alcohol, and cannabis.ResultsForty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to substance involvement, of which 67% were novel and not associated with the 6 phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine receptor D2 gene) and showed enrichment for several components of the central nervous system (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic [gamma-aminobutyric acidergic]) that are thought to …

ObjectiveSuicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.MethodsThis study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression …

BackgroundIt remains unclear how adverse childhood experiences (ACE) and increased genetic risk for bipolar disorder (BD) interact to influence BD symptom outcomes. Here we calculated multiple psychiatric polygenic risk scores (PRS) and used the measures of ACE to understand these gene-environment interactions.Method885 BD subjects were included for analyses. BD, ADHD, MDD and SCZ PRSs were calculated using the PRS-CS-auto method. ACEs were evaluated using the Children Life Event Questionnaire (CLEQ). Participants were divided into groups based on the presence of ACE and the total number of ACEs. The associations between total ACE number, PRSs and their interactions were evaluated using multiple linear and logistic regressions. Secondary analyses were performed to evaluate the influence of ACE and PRS on sub-phenotypes of BD.ResultsThe number of ACEs increased with the …

ObjectiveHepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis.DesignPatients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a …

Sleep duration has been linked to a wide range of negative health outcomes and to reduced life expectancy. We present genome-wide association studies of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration in adults of European (N = 445,966), African (N = 27,785), East Asian (N = 3141), and admixed-American (N = 16,250) ancestry from UK Biobank and the Million Veteran Programme. In a cross-population meta-analysis, we identify 84 independent loci for short sleep and 1 for long sleep. We estimate SNP-based heritability for both sleep traits in each ancestry based on population derived linkage disequilibrium (LD) scores using cov-LDSC. We identify positive genetic correlation between short and long sleep traits (rg = 0.16 ± 0.04; p = 0.0002), as well as similar patterns of genetic correlation with other psychiatric and cardiometabolic phenotypes. Mendelian randomisation reveals a …

Background and Hypothesis Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. Study Design We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic …

Along with case-control group differences in DNA methylation (DNAm) identified in epigenomewide association studies (EWAS), multiple rare DNAm outliers may exist in subsets of cases, underlying the etiological heterogeneity of some disorders. This creates an impetus for novel approaches focused on detecting rare/private outliers in the individual methylomes. Here, we present a novel, data-driven method - Outlier Methylation Analysis (OMA) – which through optimization detects genomic regions with strongly deviating DNAm levels, which we call outlier methylation regions (OMRs).Focusing on schizophrenia (SCZ) - a neuropsychiatric disorder with a heterogeneous etiology – we applied the OMA method in two independent, publicly available SCZ case-control samples with DNAm array information. We found SCZ cases had an increased burden of OMRs compared to controls (IRR=1.22, p=1.8×10-8), and case OMRs were enriched in regions relevant to cellular differentiation and development (i.e. polycomb repressed elements in the Gm12878 differentiated cell line, p=1.9×10-5, and poised promoters in the H1hesc stem cell line, p=5.4×10-4). Furthermore, SCZ cases were ~2.5-fold enriched (p=1.1×10-3) for OMRs overlapping genesets associated with developmental processes. The OMR burden was reduced in clozapine-treated, compared to untreated, SCZ cases (IRR=0.88, p=9.5×10-3), and also associated with increased chronological age (IRR=1.01, p= 2.7×10-16).Our findings demonstrate an elevated burden of OMRs in SCZ, implying methylomic dysregulation in SCZ which could correspond to the etiological heterogeneity among …

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field.We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and …

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high degree of comorbidity, including substance misuse. We aimed to assess whether ADHD polygenic risk scores (PRS) could predict ADHD diagnosis in alcohol dependence (AD). ADHD PRS were generated for 1223 AD subjects with ADHD diagnosis information and 1818 healthy controls. ADHD PRS distributions were compared to evaluate the differences between healthy controls and AD cases with and without ADHD. We found increased ADHD PRS means in the AD cohort with ADHD (mean 0.30, standard deviation (SD) 0.92; p = 3.9 × 10−6); and without ADHD (mean − 0.00, SD 1.00; p = 5.2 × 10−5) compared to the healthy control subjects (mean − 0.17, SD 0.99). The ADHD PRS means differed within the AD group with a higher ADHD PRS mean in those with ADHD, odds ratio (OR) 1.34, confidence …

BackgroundThe impact of alcohol on brain structures and functions has been well documented. However, it is unclear whether carrying the genetic risk alleles for alcohol use disorder (AUD) and alcohol consumption (AC) could have a predispositional risk for brain structures and functions.MethodsUsing the largest available set of GWAS results for alcohol use disorder and alcohol consumption, we utilised the genetic and imaging data from UK Biobank (n = 8,689), to explore the impact of AUD polygenic risk scores (AUD-PRS) and AC-PRS on brain volumes (total volumes and grey matter volumes) in individuals who drank less than 14 alcohol units per week.ResultsAfter correcting for multiple comparisons, we identified negative relationships between AUD-PRS and brain volumes of amygdala, hippocampus, thalamus, brainstem, accumbens and the 4th ventricle. We also found AUD-PRS were negatively …

Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar …

Bipolar disorder (BD) is a severe, highly heritable mental illness. The underlying mechanisms remain largely unknown. To gain greater insight, we performed the largest genome-wide association study (GWAS) meta-analyses of BD, combining clinical and community (biobank and self-report) samples of European, East Asian, African American and Latino ancestry. We detected 337 independent genome-wide significant variants mapped to 298 loci in the multi-ancestry meta-analysis, a 4-fold increase over previous findings, and a novel ancestral-specific locus in the East Asian cohort. Fine-mapping and integration of eQTL data implicated 47 credible genes in the etiology of BD. The genetic architecture of BD in community-based samples was more similar to BD type II than to BD type I, potentially reflecting a non-hospitalized, non-psychotic portion of the BD spectrum.

BackgroundThe PGC bipolar disorder working group (PGC-BD) has long recognized the importance of research into clinical sub-phenotypes in the GWAS efforts of bipolar disorder. Previous studies of BD sub-phenotypes have contributed to a better understanding of the biology of bipolar disorder and its relationship with other psychiatric disorders such as schizophrenia. In the last two years, the efforts have been refocused on additional sub-phenotypes and revitalized the data collection from more cohorts contributing to the PGC-BD. Here, we aim to present the preliminary results of the BD sub-phenotypes latest data.MethodsSub-phenotypes were identified and prioritized through discussions and a consensus was reached by PGC-BD. Sub-phenotype definitions and harmonization efforts were performed by a Clinical Expert Group. Sub-phenotype Data Management Team set up data storage and a computing …