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- Li, Dalin, et al.
(author)
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A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition
- 2016
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In: Gastroenterology. - : Saunders Elsevier. - 0016-5085 .- 1528-0012. ; 151:4, s. 724-732
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Journal article (peer-reviewed)abstract
- Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.Results: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).Conclusions: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.
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| 2. |
- Mahjani, Behrang, et al.
(author)
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Direct additive genetics and maternal effect contribute to the risk of Tourette disorder
- 2023
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 94:8, s. 638-642
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Journal article (peer-reviewed)abstract
- BACKGROUND: Risk for Tourette disorder, and chronic motor or vocal tic disorders (referenced here inclusively as CTD), arise from a combination of genetic and environmental factors. While multiple studies have demonstrated the importance of direct additive genetic variation for CTD risk, little is known about the role of cross-generational transmission of genetic risk, such as maternal effect, which is not transmitted via the inherited parental genomes. Here, we partition sources of variation on CTD risk into direct additive genetic effect (narrow-sense heritability) and maternal effect.METHODS: The study population consists of 2 522 677 individuals from the Swedish Medical Birth Register, who were born in Sweden between 1 January 1973 and 31 December 2000, and followed for a diagnosis of CTD through 31 December, 2013. We used generalised linear mixed models to partition the liability of CTD into: direct additive genetic effect, genetic maternal effect and environmental maternal effect.RESULTS: We identified 6227 (0.2%) individuals in the birth cohort with a CTD diagnosis. A study of half-siblings showed that maternal half-siblings had twice higher risk of developing a CTD compared with paternal ones. We estimated 60.7% direct additive genetic effect (95% credible interval, 58.5% to 62.4%), 4.8% genetic maternal effect (95% credible interval, 4.4% to 5.1%) and 0.5% environmental maternal effect (95% credible interval, 0.2% to 7%).CONCLUSIONS: Our results demonstrate genetic maternal effect contributes to the risk of CTD. Failure to account for maternal effect results in an incomplete understanding of the genetic risk architecture of CTD, as the risk for CTD is impacted by maternal effect which is above and beyond the risk from transmitted genetic effect.
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| 3. |
- Mahjani, Behrang, et al.
(author)
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Maternal Effects as Causes of Risk for Obsessive-Compulsive Disorder
- 2020
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 87:12, s. 1045-1051
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Journal article (peer-reviewed)abstract
- BACKGROUND: While genetic variation has a known impact on the risk for obsessive-compulsive disorder (OCD), there is also evidence that there are maternal components to this risk. Here, we partitioned sources of variation, including direct genetic and maternal effects, on risk for OCD.METHODS: The study population consisted of 822,843 individuals from the Swedish Medical Birth Register, born in Sweden between January 1, 1982, and December 31, 1990, and followed for a diagnosis of OCD through December 31, 2013. Diagnostic information about OCD was obtained using the Swedish National Patient Register.RESULTS: A total of 7184 individuals in the birth cohort (0.87%) were diagnosed with OCD. After exploring various generalized linear mixed models to fit the diagnostic data, genetic maternal effects accounted for 7.6% (95% credible interval: 6.9%-8.3%) of the total variance in risk for OCD for the best model, and direct additive genetics accounted for 35% (95% credible interval: 32.3%-36.9%). These findings were robust under alternative models.CONCLUSIONS: Our results establish genetic maternal effects as influencing risk for OCD in offspring. We also show that additive genetic effects in OCD are overestimated when maternal effects are not modeled.
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