| 1. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 2. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 3. |
- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 4. |
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| 5. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 7. |
- Watson, H. J., et al.
(författare)
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Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:8
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Tidskriftsartikel (refereegranskat)abstract
- Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness(1), affecting 0.9-4% of women and 0.3% of men(2-4), with twin-based heritability estimates of 50-60%(5). Mortality rates are higher than those in other psychiatric disorders(6), and outcomes are unacceptably poor(7). Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)(8,9) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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| 8. |
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| 9. |
- Marini, S., et al.
(författare)
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Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis
- 2019
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:4, s. 480-491
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
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| 10. |
- de Jong, S, et al.
(författare)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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