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| 2. |
- 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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| 3. |
- 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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| 4. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 5. |
- van Rheenen, Wouter, et al.
(författare)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 8. |
- van Es, Michael A, et al.
(författare)
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Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.
- 2008
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:1, s. 29-31
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Tidskriftsartikel (refereegranskat)abstract
- We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.
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| 9. |
- van Es, Michael A, et al.
(författare)
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ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis : a genome-wide association study.
- 2007
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 6:10, s. 869-77
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.
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| 10. |
- Jankovic, Nicole, et al.
(författare)
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WHO guidelines for a healthy diet and mortality from cardiovascular disease in European and American elderly : the CHANCES project
- 2015
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 102:4, s. 745-756
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cardiovascular disease (CVD) represents a leading cause of mortality worldwide, especially in the elderly. Lowering the number of CVD deaths requires preventive strategies targeted on the elderly. Objective: The objective was to generate evidence on the association between WHO dietary recommendations and mortality from CVD, coronary artery disease (CAD), and stroke in the elderly aged >= 60 y. Design: We analyzed data from 10 prospective cohort studies from Europe and the United States comprising a total sample of 281,874 men and women free from chronic diseases at baseline. Components of the Healthy Diet Indicator (HDI) included saturated fatty acids, polyunsaturated fatty acids, mono- and disaccharides, protein, cholesterol, dietary fiber, and fruit and vegetables. Cohort-specific HRs adjusted for sex, education, smoking, physical activity, and energy and alcohol intakes were pooled by using a random-effects model. Results: During 3,322,768 person-years of follow-up, 12,492 people died of CVD. An increase of 10 HDI points (complete adherence to an additional WHO guideline) was, on average, not associated with CVD mortality (HR: 0.94; 95% CI: 0.86, 1.03), CAD mortality (HR: 0.99; 95% CI: 0.85, 1.14), or stroke mortality (HR: 0.95; 95% CI: 0.88, 1.03). However, after stratification of the data by geographic region, adherence to the HDI was associated with reduced CVD mortality in the southern European cohorts (HR: 0.87; 95% CI: 0.79, 0.96; I2 = 0%) and in the US cohort (HR: 0.85; 95% CI: 0.83, 0.87; I2 = not applicable). Conclusion: Overall, greater adherence to the WHO dietary guidelines was not significantly associated with CVD mortality, but the results varied across regions. Clear inverse associations were observed in elderly populations in southein Europe and the United States.
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