Publications by authors named "Karen A Mather"

93 Publications

Novel genetic variants associated with brain functional networks in 18,445 adults from the UK Biobank.

Sci Rep 2021 07 16;11(1):14633. Epub 2021 Jul 16.

Centre for Healthy Brain Aging, CHeBA, School of Psychiatry, University of New South Wales Medicine, Kensington, Sydney, NSW, 2052, Australia.

Here, we investigated the genetics of weighted functional brain network graph theory measures from 18,445 participants of the UK Biobank (44-80 years). The eighteen measures studied showed low heritability (mean h = 0.12) and were highly genetically correlated. One genome-wide significant locus was associated with strength of somatomotor and limbic networks. These intergenic variants were located near the PAX8 gene on chromosome 2. Gene-based analyses identified five significantly associated genes for five of the network measures, which have been implicated in sleep duration, neuronal differentiation/development, cancer, and susceptibility to neurodegenerative diseases. Further analysis found that somatomotor network strength was phenotypically associated with sleep duration and insomnia. Single nucleotide polymorphism (SNP) and gene level associations with functional network measures were identified, which may help uncover novel biological pathways relevant to human brain functional network integrity and related disorders that affect it.
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http://dx.doi.org/10.1038/s41598-021-94182-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285376PMC
July 2021

Associations between nutrition and the incidence of depression in middle-aged and older adults: A systematic review and meta-analysis of prospective observational population-based studies.

Ageing Res Rev 2021 09 8;70:101403. Epub 2021 Jul 8.

Centre for Healthy Brain Ageing, UNSW, Sydney, NSW, Australia; Department of Developmental Disability Neuropsychiatry, School of Psychiatry, UNSW, Sydney, NSW, Australia.

Aim: To systematically examine the longitudinal observational evidence between diet and the incidence of depression in adults aged 45 years and older.

Method: Three electronic databases were searched for cohort studies published up to December 2020 that investigated the association between baseline dietary intake and incidence of depression in community-dwelling adults aged 45+years. Combined odds ratios (OR) and 95% confidence intervals (95%CI) were calculated. Random-effects models were used.

Results: In total 33 articles were included, with 21 combined in meta-analyses. Both the Dietary Inflammatory Index and the Western diet were associated with an increased odds of incident depression (Dietary Inflammatory Index: OR 1.33; 95%CI 1.04, 1.70; P = 0.02; Western: OR 1.15 95%CI 1.04, 1.26; P = 0.005). Higher fruit and vegetable intakes were associated with a reduced risk of incident depression (vegetables: OR 0.91; 95%CI 0.87, 0.96; P < 0.001; fruit: OR 0.85; 95%CI 0.81, 0.90; P < 0.001). No association was observed between the Mediterranean diet, "healthy" diet, fish intake and incident depression.

Conclusions: Results suggest an association between higher consumption of pro-inflammatory diets and Western diets and increased incidence of depression, while higher intake of fruit and vegetables was associated with decreased incidence of depression. These results are limited by the observational nature of the evidence (results may reflect residual confounding) and the limited number of studies. More high-quality intervention and cohort studies are needed to confirm these associations and to extend this work to other food groups and dietary patterns.
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http://dx.doi.org/10.1016/j.arr.2021.101403DOI Listing
September 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Plasma lipidome is dysregulated in Alzheimer's disease and is associated with disease risk genes.

Transl Psychiatry 2021 06 7;11(1):344. Epub 2021 Jun 7.

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, Australia.

Lipidomics research could provide insights of pathobiological mechanisms in Alzheimer's disease. This study explores a battery of plasma lipids that can differentiate Alzheimer's disease (AD) patients from healthy controls and determines whether lipid profiles correlate with genetic risk for AD. AD plasma samples were collected from the Sydney Memory and Ageing Study (MAS) Sydney, Australia (aged range 75-97 years; 51.2% male). Untargeted lipidomics analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS). We found that several lipid species from nine lipid classes, particularly sphingomyelins (SMs), cholesterol esters (ChEs), phosphatidylcholines (PCs), phosphatidylethanolamines (PIs), phosphatidylinositols (PIs), and triglycerides (TGs) are dysregulated in AD patients and may help discriminate them from healthy controls. However, when the lipid species were grouped together into lipid subgroups, only the DG group was significantly higher in AD. ChEs, SMs, and TGs resulted in good classification accuracy using the Glmnet algorithm (elastic net penalization for the generalized linear model [glm]) with more than 80% AUC. In general, group lipids and the lipid subclasses LPC and PE had less classification accuracy compared to the other subclasses. We also found significant increases in SMs, PIs, and the LPE/PE ratio in human U251 astroglioma cell lines exposed to pathophysiological concentrations of oligomeric Aβ. This suggests that oligomeric Aβ plays a contributory, if not causal role, in mediating changes in lipid profiles in AD that can be detected in the periphery. In addition, we evaluated the association of plasma lipid profiles with AD-related single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of AD. We found that FERMT2 and MS4A6A showed a significantly differential association with lipids in all lipid classes across disease and control groups. ABCA7 had a differential association with more than half of the DG lipids (52.63%) and PI lipids (57.14%), respectively. Additionally, 43.4% of lipids in the SM class were differentially associated with CLU. More than 30% of lipids in ChE, PE, and TG classes had differential associations with separate genes (ChE-PICALM, SLC24A4, and SORL1; PE-CLU and CR1; TG-BINI) between AD and control group. These data may provide renewed insights into the pathobiology of AD and the feasibility of identifying individuals with greater AD risk.
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http://dx.doi.org/10.1038/s41398-021-01362-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180517PMC
June 2021

Investigating Olfactory Gene Variation and Odour Identification in Older Adults.

Genes (Basel) 2021 04 29;12(5). Epub 2021 Apr 29.

Centre for Healthy Brain Ageing, Faculty of Medicine, School of Psychiatry, University of New South Wales (UNSW), Sydney, NSW 2031, Australia.

Ageing is associated with a decrease in odour identification. Additionally, deficits in olfaction have been linked to age-related disease and mortality. Heritability studies suggest genetic variation contributes to olfactory identification. The olfactory receptor (OR) gene family is the largest in the human genome and responsible for overall odour identification. In this study, we sought to find olfactory gene family variants associated with individual and overall odour identification and to examine the relationships between polygenic risk scores (PRS) for olfactory-related phenotypes and olfaction. Participants were Caucasian older adults from the Sydney Memory and Ageing Study and the Older Australian Twins Study with genome-wide genotyping data ( = 1395, mean age = 75.52 ± 6.45). The Brief-Smell Identification Test (BSIT) was administered in both cohorts. PRS were calculated from independent GWAS summary statistics for Alzheimer's disease (AD), white matter hyperintensities (WMH), Parkinson's disease (PD), hippocampal volume and smoking. Associations with olfactory receptor genes ( = 967), previously identified candidate olfaction-related SNPs ( = 36) and different PRS with BSIT scores (total and individual smells) were examined. All of the relationships were analysed using generalised linear mixed models (GLMM), adjusted for age and sex. Genes with suggestive evidence for odour identification were found for 8 of the 12 BSIT items. Thirteen out of 36 candidate SNPs previously identified from the literature were suggestively associated with several individual BSIT items but not total score. PRS for smoking, WMH and PD were negatively associated with chocolate identification. This is the first study to conduct genetic analyses with individual odorant identification, which found suggestive olfactory-related genes and genetic variants for multiple individual BSIT odours. Replication in independent and larger cohorts is needed.
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http://dx.doi.org/10.3390/genes12050669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145954PMC
April 2021

Polygenic risk score analysis for amyotrophic lateral sclerosis leveraging cognitive performance, educational attainment and schizophrenia.

Eur J Hum Genet 2021 Apr 27. Epub 2021 Apr 27.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R) of the case-control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R) of 0.027 (P value = 4.6 × 10), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96-5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS.
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http://dx.doi.org/10.1038/s41431-021-00885-yDOI Listing
April 2021

The influence of rs53576 polymorphism in the oxytocin receptor () gene on empathy in healthy adults by subtype and ethnicity: a systematic review and meta-analysis.

Rev Neurosci 2021 Apr 23. Epub 2021 Apr 23.

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia.

Empathy is essential for navigating complex social environments. Prior work has shown associations between rs53576, a single nucleotide polymorphism (SNP) located in the oxytocin receptor gene (), and generalized empathy. We undertook a systematic review and meta-analysis to assess the effects of rs53576 on subdomains of empathy, specifically cognitive empathy (CE) and affective empathy (AE), in healthy adults. Twenty cohorts of 8933 participants aged 18-98 were identified, including data from the Sydney Memory and Ageing Study, a cohort of older community adults. Meta-analyses found G homozygotes had greater generalized empathic abilities only in young to middle-aged adults. While meta-analyses of empathy subdomains yielded no significant overall effects, there were differential effects based on ethnicity. G homozygotes were associated with greater CE abilities in Asian cohorts (standardized mean difference; SMD: 0.09 [2.8·10-0.18]), and greater AE performance in European cohorts [SMD: 0.12 (0.04-0.21)]. The current literature highlights a need for further work that distinguishes between genetic and ethnocultural effects and explores effects of advanced age on this relationship.
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http://dx.doi.org/10.1515/revneuro-2021-0038DOI Listing
April 2021

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 03 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

Hum Brain Mapp 2021 Feb 21. Epub 2021 Feb 21.

Center for Neuroimaging, Genetics and Genomics, School of Psychology, NUI Galway, Galway, Ireland.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
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http://dx.doi.org/10.1002/hbm.25354DOI Listing
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Associations between Alzheimer's disease polygenic risk scores and hippocampal subfield volumes in 17,161 UK Biobank participants.

Neurobiol Aging 2021 02 6;98:108-115. Epub 2020 Nov 6.

Centre for Healthy Brain Aging (CHeBA), School of Psychiatry, University of New South Wales Medicine, Kensington, Sydney, New South Wales, Australia; Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Randwick, Sydney, New South Wales, Australia.

Hippocampal volume is an important biomarker of Alzheimer's disease (AD), and genetic risk of AD is associated with hippocampal atrophy. However, the hippocampus is not a uniform structure and has a number of subfields, the associations of which with age, sex, and polygenic risk score for AD (PRS) have been inadequately investigated. We examined these associations in 17,161 cognitively normal UK Biobank participants (44-80 years). Age was negatively associated with all the hippocampal subfield volumes and females had smaller volumes than men. Higher PRS was associated with lower volumes in the bilateral whole hippocampus, hippocampal-amygdala-transition-area, and hippocampal tail; right subiculum; left cornu ammonis 1, cornu ammonis 4, molecular layer, and granule cell layer of dentate gyrus. Older individuals (median age 63 years, n = 8984) showed greater subfield vulnerability to high PRS compared to the younger group (n = 8177), but the effect did not differ by sex. The pattern of subfield involvement in relation to the PRS in community dwelling healthy individuals sheds additional light on the pathogenesis of AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.002DOI Listing
February 2021

Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.

Cell Rep 2020 10;33(4):108323

Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane QLD, Australia.

We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients' fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: -2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: -1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients.
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http://dx.doi.org/10.1016/j.celrep.2020.108323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610013PMC
October 2020

Genetic and environmental causes of variation in epigenetic aging across the lifespan.

Clin Epigenetics 2020 10 22;12(1):158. Epub 2020 Oct 22.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3051, Australia.

Background: DNA methylation-based biological age (DNAm age) is an important biomarker for adult health. Studies in specific age ranges have found widely varying results about its genetic and environmental causes of variation. However, these studies are not able to provide a comprehensive view of the causes of variation over the lifespan.

Results: In order to investigate the genetic and environmental causes of DNAm age variation across the lifespan, we pooled genome-wide DNA methylation data for 4217 people aged 0-92 years from 1871 families. DNAm age was calculated using the Horvath epigenetic clock. We estimated familial correlations in DNAm age for monozygotic (MZ) twin, dizygotic (DZ) twin, sibling, parent-offspring, and spouse pairs by cohabitation status. Genetic and environmental variance components models were fitted and compared. We found that twin pair correlations were - 0.12 to 0.18 around birth, not different from zero (all P > 0.29). For all pairs of relatives, their correlations increased with time spent living together (all P < 0.02) at different rates (MZ > DZ and siblings > parent-offspring; P < 0.001) and decreased with time spent living apart (P = 0.02) at similar rates. These correlation patterns were best explained by cohabitation-dependent shared environmental factors, the effects of which were 1.41 (95% confidence interval [CI] 1.16 to 1.66) times greater for MZ pairs than for DZ and sibling pairs, and the latter were 2.03 (95% CI 1.13 to 9.47) times greater than for parent-offspring pairs. Genetic factors explained 13% (95% CI - 10 to 35%) of variation (P = 0.27). Similar results were found for another two epigenetic clocks, suggesting that our observations are robust to how DNAm age is measured. In addition, results for the other clocks were consistent with there also being a role for prenatal environmental factors in determining their variation.

Conclusions: Variation in DNAm age is mostly caused by environmental factors, including those shared to different extents by relatives while living together and whose effects persist into old age. The equal environment assumption of the classic twin study might not hold for epigenetic aging.
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http://dx.doi.org/10.1186/s13148-020-00950-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583207PMC
October 2020

Risk prediction of late-onset Alzheimer's disease implies an oligogenic architecture.

Nat Commun 2020 09 23;11(1):4799. Epub 2020 Sep 23.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (P) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.
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http://dx.doi.org/10.1038/s41467-020-18534-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511365PMC
September 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins.

Elife 2020 07 22;9. Epub 2020 Jul 22.

Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.

The critical role of blood lipids in a broad range of health and disease states is well recognised but less explored is the interplay of genetics and environment within the broader blood lipidome. We examined heritability of the plasma lipidome among healthy older-aged twins (75 monozygotic/55 dizygotic pairs) enrolled in the Older Australian Twins Study (OATS) and explored corresponding gene expression and DNA methylation associations. 27/209 lipids (13.3%) detected by liquid chromatography-coupled mass spectrometry (LC-MS) were significantly heritable under the classical ACE twin model (h = 0.28-0.59), which included ceramides (Cer) and triglycerides (TG). Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for variability in some non-heritable lipids. We reveal a complex interplay of genetic and environmental influences on the ageing plasma lipidome.
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http://dx.doi.org/10.7554/eLife.58954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394543PMC
July 2020

Development of a short-form version of the Reading the Mind in the Eyes Test for assessing theory of mind in older adults.

Int J Geriatr Psychiatry 2020 11 30;35(11):1322-1330. Epub 2020 Jul 30.

Centre for Healthy Brain Ageing (CheBA), School Of Psychiatry, University of New South Wales, Sydney, New South Wales, 2052, Australia.

Background: The Reading the Mind in the Eyes test (RMET) is a 36-item assessment for theory of mind (ToM) performance. While this measure has been shown to be sensitive to age-related ToM difficulties, there are no established cutoffs or guidelines currently available that are specific to older adults. This article seeks to validate a short-form version of the RMET appropriate for use in such populations.

Methods: Cross-sectional data from 295 participants (mean age 86 years) from the Sydney Memory and Ageing Study, a longitudinal community observational cohort. Participants underwent an assessment battery that included the RMET. Individuals who scored >1SD below the RMET scores of cognitively normal participants were deemed to have below average RMET scores. Various model-building methods were used to generate short-form solutions of the RMET, which were compared with previously validated versions in their predictive power for below average full RMET performance.

Results: Individuals with below average RMET performance tended to be older and have poorer global cognition. Of the eight short-form solutions, the 21-item version generated using genetic algorithm exhibited the best classification performance with an area under the receiver operating curve (AUROC) of 0.98 and had 93.2% accuracy in classifying individuals with below average ToM. A shorter 10-item solution derived by ant colony optimization also had acceptable performance.

Conclusion: We recommend the 21-item version of the RMET for use in older adult populations for identifying individuals with impaired ToM. Where an even shorter version is needed with a trade-off of slightly reduced performance, the 10-item version is acceptable.
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http://dx.doi.org/10.1002/gps.5369DOI Listing
November 2020

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

Stroke 2020 07 10;51(7):2111-2121. Epub 2020 Jun 10.

Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.

Background And Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.

Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.

Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (), 10q23.1 (), and 10q24.33 ( In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 () and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: (2q32.1), (3q27.1), (5q27.1), and (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.

Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
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http://dx.doi.org/10.1161/STROKEAHA.119.027544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365038PMC
July 2020

Differential blood miRNA expression in brain amyloid imaging-defined Alzheimer's disease and controls.

Alzheimers Res Ther 2020 05 15;12(1):59. Epub 2020 May 15.

Centre for Healthy Brain and Ageing, University of New South Wales, Sydney, Australia.

Background: Peripheral blood microRNAs (miRNA) have been identified as potential biomarkers for Alzheimer's disease (AD). Study results have generally been inconsistent and limited by sample heterogeneity. The aim of this study is to establish candidate blood miRNA biomarkers for AD by comparing differences in miRNA expression between participants with brain amyloid imaging-defined AD and normal cognition.

Methods: Blood RNA was extracted from a subset of participants from the Australian Imaging Biomarkers Lifestyle Study of Ageing cohort (AIBL) with brain amyloid imaging results. MiRNA profiling was performed using small RNA sequencing on 71 participants, comprising 40 AD with high brain amyloid burden on imaging (amyloid positive) and 31 cognitively normal controls with low brain amyloid burden (amyloid negative). Cross-sectional comparisons were made between groups to examine differential miRNA expression levels using Fisher's exact tests. Replication of results was undertaken using a publicly available dataset of blood miRNA data of AD and controls. In silico analysis of downstream messenger RNA targets of candidate miRNAs was performed to elucidate potential biological function.

Results: After quality control, 816 miRNAs were available for analysis. There were 71 significantly differentially expressed miRNAs between the AD and control groups (p < 0.05). Two of these miRNAs, miR-146b-5p and miR-15b-5p, were also significant in the replication cohort. Pathways analysis showed these miRNAs to be involved in innate immune system and regulation of the cell cycle, respectively, both of which have relevance to AD pathogenesis.

Conclusion: Blood miR-146b-5p and miR15b-5p showed consistent differential expression in AD compared to controls. Further replication and translational studies in strictly phenotyped cohorts are needed to establish their role as biomarkers for AD to have clinical utility.
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http://dx.doi.org/10.1186/s13195-020-00627-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229622PMC
May 2020

Unraveling the genetic contributions to complex traits across different ethnic groups.

Nat Med 2020 04;26(4):467-469

Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.

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http://dx.doi.org/10.1038/s41591-020-0834-3DOI Listing
April 2020

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

Cereb Cortex 2020 06;30(7):4121-4139

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04109 Leipzig, Germany.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.
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http://dx.doi.org/10.1093/cercor/bhaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947185PMC
June 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Genetic influence on ageing-related changes in resting-state brain functional networks in healthy adults: A systematic review.

Neurosci Biobehav Rev 2020 06 10;113:98-110. Epub 2020 Mar 10.

Centre for Healthy Brain Aging, CHeBA, School of Psychiatry, University of New South Wales Medicine, Kensington, New South Wales, 2052, Sydney, Australia; Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Randwick, New South Wales, 2031, Sydney, Australia.

This systematic review examines the genetic and epigenetic factors associated with resting-state functional connectivity (RSFC) in healthy human adult brains across the lifespan, with a focus on genes associated with Alzheimer's disease (AD). There were 58 studies included. The key findings are: (i) genetic factors have a low to moderate contribution; (ii) the apolipoprotein E ε2/3/4 polymorphism was the most studied genetic variant, with the APOE-ε4 allele most consistently associated with deficits of the default mode network, but there were insufficient studies to determine the relationships with other AD candidate risk genes; (iii) a single genome-wide association study identified several variants related to RSFC; (iv) two epigenetic independent studies showed a positive relationship between blood DNA methylation of the SLC6A4 promoter and RSFC measures. Thus, there is emerging evidence that genetic and epigenetic variation influence the brain's functional organisation and connectivity over the adult lifespan. However, more studies are required to elucidate the roles genetic and epigenetic factors play in RSFC measures across the adult lifespan.
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http://dx.doi.org/10.1016/j.neubiorev.2020.03.011DOI Listing
June 2020

Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis.

NPJ Genom Med 2020 27;5:10. Epub 2020 Feb 27.

4Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW 2109 Australia.

We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case-control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case-control status in the Netherlands sample (area under the curve, AUC = 0.65, CI = [0.62-0.68],  = 8.3 × 10). The maximum AUC achieved was 0.69 (CI = [0.66-0.71],  = 4.3 × 10) when cell-type proportion was included in the predictor.
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http://dx.doi.org/10.1038/s41525-020-0118-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046630PMC
February 2020

Downregulated transferrin receptor in the blood predicts recurrent MDD in the elderly cohort: A fuzzy forests approach.

J Affect Disord 2020 04 5;267:42-48. Epub 2020 Feb 5.

Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. Electronic address:

Background: At present, no predictive markers for Major Depressive Disorder (MDD) exist. The search for such markers has been challenging due to clinical and molecular heterogeneity of MDD, the lack of statistical power in studies and suboptimal statistical tools applied to multidimensional data. Machine learning is a powerful approach to mitigate some of these limitations.

Methods: We aimed to identify the predictive markers of recurrent MDD in the elderly using peripheral whole blood from the Sydney Memory and Aging Study (SMAS) (N = 521, aged over 65) and adopting machine learning methodology on transcriptome data. Fuzzy Forests is a Random Forests-based classification algorithm that takes advantage of the co-expression network structure between genes; it allows to alleviate the problem of p >> n via reducing the dimensionality of transcriptomic feature space.

Results: By adopting Fuzzy Forests on transcriptome data, we found that the downregulated TFRC (transferrin receptor) can predict recurrent MDD with an accuracy of 63%.

Limitations: Although we corrected our data for several important confounders, we were not able to account for the comorbidities and medication taken, which may be numerous in the elderly and might have affected the levels of gene transcription.

Conclusions: We found that downregulated TFRC is predictive of recurrent MDD, which is consistent with the previous literature, indicating the role of the innate immune system in depression. This study is the first to successfully apply Fuzzy Forests methodology on psychiatric condition, opening, therefore, a methodological avenue that can lead to clinically useful predictive markers of complex traits.
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http://dx.doi.org/10.1016/j.jad.2020.02.001DOI Listing
April 2020

Going around in circles: deciphering the role of circular RNAs in neurodegenerative disease.

Curr Opin Psychiatry 2020 Mar;33(2):141-147

Centre for Healthy Brain Ageing, University of New South Wales, Sydney.

Purpose Of Review: Circular RNAs are highly expressed in the brain, accumulate with ageing and may play important functional roles. Hence, their role in age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, is under active investigation. This review provides an overview of our current knowledge regarding the roles of circular RNAs in Alzheimer's disease and Parkinson's disease.

Recent Findings: More studies have examined Alzheimer's disease than Parkinson's disease. Circular RNA 7 (ciRS-7) has been implicated in both diseases and may play a causative pathological role in at least Alzheimer's disease. The identification of circular RNA interaction networks is a primary focus. However, different analysis pipelines can generate quite disparate results, hence bioinformatically identified candidate circular RNAs require experimental and functional validation.

Summary: Although this field of research is in its infancy, rapid advances holds promise for identifying circular RNAs that are important in neurodegenerative diseases. CiRS-7 is a promising candidate for further examination. More studies are required focussing not only on Alzheimer's disease and Parkinson's disease but also on other neurodegenerative diseases. Whether circular RNAs can be used to inform diagnostic, prognostic and therapeutic strategies for age-related neurodegenerative disease remains unclear.
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http://dx.doi.org/10.1097/YCO.0000000000000582DOI Listing
March 2020

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

Mol Psychiatry 2019 Dec 6. Epub 2019 Dec 6.

University Medical Centre Hamburg-Eppendorf, House W34, 3.OG, Martinistr. 52, 20246, Hamburg, Germany.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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http://dx.doi.org/10.1038/s41380-019-0605-zDOI Listing
December 2019

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

JAMA Psychiatry 2020 04;77(4):420-430

Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, And Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes And Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions And Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.3779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822096PMC
April 2020
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