0026 Strong Gene-Environment Interactions of Trank1 Gene Polymorphisms with Birth Difficulties in Kleine Levin Syndrome

Abstract Introduction Kleine-Levin Syndrome (KLS) is a rare disorder affecting adolescents and characterized by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, and behavioral disturbances such as hyperphagia and sexual disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas and in cortical areas during episodes. Familial occurrence is increased, and risk is associated with reports of complicated birth. Methods A worldwide Genome wide association (GWA) study was conducted in 673 KLS patients and ethnically matched 15,341 control individuals. Results We found a strong genome-wide significant association (OR=1.48 at rs150168018, p=8.6x10-9) with 24 single nucleotide polymorphisms (SNPs) encompassing a 35kb region located in the 5’ region of TRANK1 gene previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with TRANK1 had statistically increased reports of difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years, and found that recent cases had a significantly reduced TRANK1 association. These findings were confirmed in an independent replication cohort of 171 new patients where polygenic risk scores constructed on the discovery cohort replicated (r2=0.15; p<2.7x10-22 at p=0.1 threshold) and the TRANK1 association was found to be dependent on reports of birth difficulties (OR=1.54, p=0.01 versus OR=1.12, p=0.4). Pathway analysis of the overall GWAS association revealed significant association (p=0.02) with 19 genes in a pathway modulating rhythmic behaviors. Conclusion Our results demonstrate links between hypersomnia, behavioral rhythmicity and bipolar disorder and indicate that a polymorphism in the TRANK1 region affect brain development in the presence of a perinatal injury, with pathophysiological consequences such as KLS, bipolar disorder and schizophrenia. Support NIH NIMH 1R01MH080957 to EM PHRC 070138 to IA

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Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005753118 ◽

2021 ◽

Vol 118 (12) ◽

pp. e2005753118

Author(s):

Aditya Ambati ◽

Ryan Hillary ◽

Smaranda Leu-Semenescu ◽

Hanna M. Ollila ◽

Ling Lin ◽

...

Keyword(s):

Bipolar Disorder ◽

Genome Wide Association Study ◽

Perinatal Outcomes ◽

Case Control ◽

Risk Scores ◽

Circadian Regulation ◽

Genetic Associations ◽

Imaging Studies ◽

Genome Wide

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case−control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10−9) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10−22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

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Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

10.1101/2021.01.08.20249006 ◽

2021 ◽

Author(s):

Aditya Ambati ◽

Ryan Hillary ◽

Smaranda Leu-Semenescu ◽

Hanna M. Ollila ◽

Ling Lin ◽

...

Keyword(s):

Bipolar Disorder ◽

Genome Wide Association Study ◽

Lithium Treatment ◽

Gene Region ◽

Risk Scores ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Genome Wide ◽

Increased Risk

AbstractKleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome wide association study in 673 KLS cases collected over 14 years, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (OR=1.48,rs71947865,p=8.6×10−9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3’ region of TRANK1 gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with TRANK1 rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years and found that recent cases had a significantly reduced TRANK1 rs71947865 association. While theTRANK1 rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, the TRANK1 rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR=1.54;p=0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo r2=0.15;p<2.0×10−22 at p=0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, behavioral rhythmicity, and bipolar disorder, and indicates that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.Significance StatementGenetic markers in TRANK1 gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin Syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment are suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in the TRANK1 gene region may predispose to KLS when patients have had a difficult birth, suggesting that TRANK1 gene region modulate newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impact birth and KLS.

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Pharmacogenomics of Lithium Response in Bipolar Disorder

Pharmaceuticals ◽

10.3390/ph14040287 ◽

2021 ◽

Vol 14 (4) ◽

pp. 287

Author(s):

Courtney M. Vecera ◽

Gabriel R. Fries ◽

Lokesh R. Shahani ◽

Jair C. Soares ◽

Rodrigo Machado-Vieira

Keyword(s):

Bipolar Disorder ◽

Association Studies ◽

Mood Stabilizer ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Non Coding Rna ◽

Genome Wide ◽

Lithium Response ◽

Genetic Loading ◽

Long Non Coding Rna

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

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Effect of polygenic risk scores on depression in childhood trauma

The British Journal of Psychiatry ◽

10.1192/bjp.bp.113.143081 ◽

2014 ◽

Vol 205 (2) ◽

pp. 113-119 ◽

Cited By ~ 105

Author(s):

Wouter J. Peyrot ◽

Yuri Milaneschi ◽

Abdel Abdellaoui ◽

Patrick F. Sullivan ◽

Jouke J. Hottenga ◽

...

Keyword(s):

Childhood Trauma ◽

Meta Analysis ◽

Genetic Effect ◽

Risk Scores ◽

Environment Interaction ◽

Polygenic Risk ◽

Gene Environment Interaction ◽

Gene Environment ◽

Genome Wide ◽

Direct Genetic Effect

BackgroundResearch on gene×environment interaction in major depressive disorder (MDD) has thus far primarily focused on candidate genes, although genetic effects are known to be polygenic.AimsTo test whether the effect of polygenic risk scores on MDD is moderated by childhood trauma.MethodThe study sample consisted of 1645 participants with a DSM-IV diagnosis of MDD and 340 screened controls from The Netherlands. Chronic or remitted episodes (severe MDD) were present in 956 participants. The occurrence of childhood trauma was assessed with the Childhood Trauma Interview and the polygenic risk scores were based on genome-wide meta-analysis results from the Psychiatric Genomics Consortium.ResultsThe polygenic risk scores and childhood trauma independently affected MDD risk, and evidence was found for interaction as departure from both multiplicativity and additivity, indicating that the effect of polygenic risk scores on depression is increased in the presence of childhood trauma. The interaction effects were similar in predicting all MDD risk and severe MDD risk, and explained a proportion of variation in MDD risk comparable to the polygenic risk scores themselves.ConclusionsThe interaction effect found between polygenic risk scores and childhood trauma implies that (1) studies on direct genetic effect on MDD gain power by focusing on individuals exposed to childhood trauma, and that (2) individuals with both high polygenic risk scores and exposure to childhood trauma are particularly at risk for developing MDD.

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Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa133 ◽

2020 ◽

Author(s):

Tim B Bigdeli ◽

Ayman H Fanous ◽

Yuli Li ◽

Nallakkandi Rajeevan ◽

Frederick Sayward ◽

...

Keyword(s):

Bipolar Disorder ◽

Association Studies ◽

Genome Wide Association ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Susceptibility Loci ◽

New Associations ◽

Genome Wide ◽

Us Veterans

Abstract Background Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world’s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. Methods We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. Results Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10–30) and African American (P < .0005) participants in CSP #572. Conclusions We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

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Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes

10.1101/173435 ◽

2017 ◽

Author(s):

Douglas M Ruderfer ◽

Stephan Ripke ◽

Andrew McQuillin ◽

James Boocock ◽

Eli A Stahl ◽

...

Keyword(s):

Bipolar Disorder ◽

Negative Symptoms ◽

Age Of Onset ◽

Significant Proportion ◽

Genomic Region ◽

Risk Scores ◽

Sign Test ◽

Specific Symptom ◽

Genome Wide ◽

Psychotic Features

AbstractSchizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2×10−6) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6×10−6) and manic symptoms (BD, p=2×10−5), 2) BD subphenotypes: psychotic features (SCZ p=1.2×10−10, BD p=5.3×10−5) and age of onset (SCZ p=7.9×10−4). Finally, we show that psychotic features in BD has significant SNP-heritability (h2snp=0.15, SE=0.06), and a significant genetic correlation with SCZ (rg=0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes (DARS2, ARFGEF2, DCAKD and GATAD2A) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.

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Re-analysis of a Genome-Wide Gene-By-Environment Interaction Study of Case Parent Trios, Adjusted for Population Stratification

Frontiers in Genetics ◽

10.3389/fgene.2020.600232 ◽

2021 ◽

Vol 11 ◽

Author(s):

Pulindu Ratnasekera ◽

Brad McNeney

Keyword(s):

East Asian ◽

Environment Interaction ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Multivitamin Supplementation ◽

Gene Environment ◽

Genome Wide ◽

A Genome ◽

The Impact ◽

East Asian Ancestry

We investigate the impact of confounding on the results of a genome-wide association analysis by Beaty et al., which identified multiple single nucleotide polymorphisms that appeared to modify the effect of maternal smoking, alcohol consumption, or multivitamin supplementation on risk of cleft palate. The study sample of case-parent trios was primarily of European and East Asian ancestry, and the distribution of all three exposures differed by ancestral group. Such differences raise the possibility that confounders, rather than the exposures, are the risk modifiers and hence that the inference of gene-environment (G×E) interaction may be spurious. Our analyses generally confirmed the result of Beaty et al. and suggest the interaction G×E is driven by the European trios, whereas the East Asian trios were less informative.

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Abstract P127: Gene-Lifestyle Interactions Detect Novel Blood Pressure Loci

Circulation ◽

10.1161/circ.137.suppl_1.p127 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Oyomoare L Osazuwa-Peters ◽

Karen L Schwander ◽

Yun J Sung ◽

Lisa de las Fuentes ◽

Dabeeru C Rao

Keyword(s):

Blood Pressure ◽

Interaction Analysis ◽

Smoking Status ◽

Interaction Effects ◽

Lifestyle Factors ◽

Risk Scores ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

Heart Study

Introduction: Gene-lifestyle interaction effects (GxE more generally) on blood pressure (BP), a promising approach for novel loci discovery, is being actively pursued in the CHARGE Gene-Lifestyle Interactions Working Group using individual lifestyle domains, such as smoking status. Objectives: To explore the potential utility of a “lifestyle index” (aggregating multiple lifestyle domains) for identifying novel BP loci in a GxE context, we performed genome-wide interaction analysis with two lifestyle index variables. Methods: For each of 6,257 subjects (19 – 80 years, 46.9% male) in the Framingham Heart Study SHARe dataset, lifestyle index was defined as the sum of risk scores for four lifestyle factors: smoking status (0 = Never, 1 = Former, 2 = Current), alcohol intake (0 = Moderate, 1 = Never, 2 = Heavy), physical activity (0 = Active, 1= Inactive), and educational level (0=College degree, 1 = Some college, and 2 = No college). We examined GxE for systolic BP using the quantitative index (ranging from 0 to 7) and a binary form of the index (≥ vs < the median), while adjusting for sex, age, and kinship. Promising loci were identified using a 2 df joint test of main and interaction effects at α = 5 x 10 -6 . Results: Sixteen promising single nucleotide polymorphisms (SNPs) representing 8 loci were found when using the quantitative lifestyle index, and 43 SNPs representing 4 loci when using the binary lifestyle index (Table 1), with only one locus common to both indices. Of the 11 unique loci detected, 3 are within 500 kb of known BP loci and 6 are in or near a gene with a known function. Conclusions: We demonstrate that a composite of multiple lifestyle factors can enhance novel discovery.

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Genetics of Cardiovascular Disease: How Far Are We from Personalized CVD Risk Prediction and Management?

International Journal of Molecular Sciences ◽

10.3390/ijms22084182 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4182

Author(s):

Michal Vrablik ◽

Dana Dlouha ◽

Veronika Todorovova ◽

Denes Stefler ◽

Jaroslav A. Hubacek

Keyword(s):

Cardiovascular Disease ◽

Risk Prediction ◽

Association Studies ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Cvd Risk ◽

Mortality And Morbidity ◽

New Genes ◽

Gene Environment ◽

Genome Wide

Despite the rapid progress in diagnosis and treatment of cardiovascular disease (CVD), this disease remains a major cause of mortality and morbidity. Recent progress over the last two decades in the field of molecular genetics, especially with new tools such as genome-wide association studies, has helped to identify new genes and their variants, which can be used for calculations of risk, prediction of treatment efficacy, or detection of subjects prone to drug side effects. Although the use of genetic risk scores further improves CVD prediction, the significance is not unambiguous, and some subjects at risk remain undetected. Further research directions should focus on the “second level” of genetic information, namely, regulatory molecules (miRNAs) and epigenetic changes, predominantly DNA methylation and gene-environment interactions.

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