| 1. |
- Gopalakrishnan, Shyam, et al.
(författare)
-
The population genomic legacy of the second plague pandemic
- 2022
-
Ingår i: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445. ; 32:21, s. 4743-4751.e6
-
Tidskriftsartikel (refereegranskat)abstract
- Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.
|
|
| 2. |
- Mullins, Niamh, et al.
(författare)
-
GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
- 2019
-
Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
|
|
| 3. |
- Rodríguez-Varela, Ricardo, et al.
(författare)
-
The genetic history of Scandinavia from the Roman Iron Age to the present
- 2023
-
Ingår i: Cell. - : Elsevier. - 0092-8674 .- 1097-4172. ; 186:1, s. 32-46
-
Tidskriftsartikel (refereegranskat)abstract
- We investigate a 2,000-year genetic transect through Scandinavia spanning the Iron Age to the present, based on 48 new and 249 published ancient genomes and genotypes from 16,638 modern individuals. We find regional variation in the timing and magnitude of gene flow from three sources: the eastern Baltic, the British-Irish Isles, and southern Europe. British-Irish ancestry was widespread in Scandinavia from the Viking period, whereas eastern Baltic ancestry is more localized to Gotland and central Sweden. In some regions, a drop in current levels of external ancestry suggests that ancient immigrants contributed proportionately less to the modern Scandinavian gene pool than indicated by the ancestry of genomes from the Viking and Medieval periods. Finally, we show that a north-south genetic cline that characterizes modern Scandinavians is mainly due to the differential levels of Uralic ancestry and that this cline existed in the Viking Age and possibly earlier.
|
|
| 4. |
|
|
| 5. |
- Jönsson, Erik G., et al.
(författare)
-
Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder : An association study
- 2008
-
Ingår i: American journal of medical genetics. Part B, Neuropsychiatric genetics. - : Wiley. - 1552-4841. ; 147B:6, s. 976-982
-
Tidskriftsartikel (refereegranskat)abstract
- Recent meta-analyses of the methylenetetrahydrofolate reductase gene (MTHFR) have suggested association between two of its functional single gene polymorphisms (SNPs, C677T and A1298C) and schizophrenia. Studies have also suggested association between MTHFR C677T and A1298C variation and bipolar disorder. In a replication attempt the MTHFR C677T and A1298C SNPs were analyzed in three Scandinavian schizophrenia case-control samples. In addition, Norwegian patients with bipolar disorder were investigated. There were no statistically significant allele or genotype case-control differences. The present Scandinavian results do not verify previous associations between the putative functional MTHFR gene polymorphisms and schizophrenia or bipolar disorder. However, when combined with previous studies in meta-analyses there is still evidence for association between the MTHFR C677T polymorphism. and schizophrenia. Additional studies are warranted to shed further light on these relationships. (c) 2007 Wiley-Liss, Inc.
|
|
| 6. |
- Saetre, Peter, et al.
(författare)
-
The Tryptophan Hydroxylase 1 (TPH1) Gene, Schizophrenia Susceptibility, and Suicidal Behavior : A Multi-Centre Case-Control Study and Meta-Analysis
- 2010
-
Ingår i: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 153B:2, s. 387-396
-
Tidskriftsartikel (refereegranskat)abstract
- Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P=0.84). A systematic literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07-1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I-2 = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80-1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.
|
|
| 7. |
- Skotte, Line, et al.
(författare)
-
Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes
- 2022
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:2, s. 555-568
-
Tidskriftsartikel (refereegranskat)abstract
- Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
|
|
| 8. |
- Van Schijndel, Jessica E., et al.
(författare)
-
Dual association of a TRKA polymorphism with schizophrenia
- 2011
-
Ingår i: Psychiatric Genetics. - : Lippincott Williams & Wilkins. - 0955-8829 .- 1473-5873. ; 21:3, s. 125-131
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor.METHODS: We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups.RESULT: Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor.CONCLUSION: An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors.
|
|
| 9. |
- Vares, Maria, et al.
(författare)
-
Association Between Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Age of Onset in Schizophrenia
- 2010
-
Ingår i: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 153B:2, s. 610-618
-
Tidskriftsartikel (refereegranskat)abstract
- Different lines of evidence indicate that methylenetetrahydrofolate reductase (MTHFR) functional gene polymorphisms, causative in aberrant folate-homocysteine metabolism, are associated with increased vulnerability to several heritable developmental disorders. Opposing views are expressed considering the possible association between MTHFR and susceptibility for schizophrenia. In order to evaluate if age of onset could explain some of this discrepancy we investigated the relationship between two functional MTHFR gene polymorphisms and age at onset in this disorder. Scandinavian patients (n = 820) diagnosed with schizophrenia, schizoaffective disorder, and schizophreniform disorder were investigated. Two functional MTHFR single nucleotide polymorphisms (SNPs; rs1801131 and rs1801133) were genotyped and the effect of MTHFR polymorphisms on the age of onset was examined with survival analysis. In an attempt to replicate the findings from the Scandinavian sample, the association between rs1801133 and age at onset was also analyzed in Chinese high-risk families, with two or more affected siblings (n = 243). Among the Scandinavian patients the functional MTHFR SNP rs1801133 (C677T) significantly affected age at onset of schizophrenia in a dose-dependent manner (P = 0.0015), with lower age of onset with increasing numbers of the mutant T-allele. There was no evidence of rs1801131 (A1298C) affecting age of onset in schizophrenia. Within the Chinese high-risk families carriers of the MTHFR 677T allele showed earlier age at onset than siblings being homozygous for the wild-type allele (P = 0.008). The MTHFR C677T polymorphism may play a role as a modifying factor for age of onset in schizophrenia.
|
|
