ORCID Profile
0000-0002-4496-6451
Current Organisations
Karolinska Institutet
,
University of Gothenburg
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Publisher: Research Square Platform LLC
Date: 26-06-2023
DOI: 10.21203/RS.3.RS-3068352/V1
Abstract: The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi + Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p 1x10 − 4 values, including HAS3 , CNTNAP5 and NFIB . Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4 , XKR4 , NRXN1 , NRG1/3 and GRK5 . Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.
Publisher: Research Square Platform LLC
Date: 31-03-2023
DOI: 10.21203/RS.3.RS-2720355/V1
Abstract: Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 in iduals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.
Publisher: Research Square Platform LLC
Date: 03-10-2023
Publisher: Springer Science and Business Media LLC
Date: 16-10-2020
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2020
DOI: 10.1101/2020.08.13.249813
Abstract: 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. We conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815 p =3.2×10 −8 ), that interacts with sodium otassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence ( p ×10 −6 ) for cross-disorder GxS 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 GxS 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 GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD ( p FDR .05). In the largest genome-wide GxS 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, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Publisher: Cambridge University Press (CUP)
Date: 05-04-2022
DOI: 10.1017/S0033291721004554
Abstract: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and erse clinical biobank populations with electronic health record phenotypes. Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai Bio Me ™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations. Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex. Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2200
DOI: 10.1038/S41380-020-0689-5
Abstract: Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi
Publisher: Springer Science and Business Media LLC
Date: 11-07-2022
Publisher: Springer Science and Business Media LLC
Date: 28-09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 18-02-2021
DOI: 10.1101/2021.02.12.21250941
Abstract: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional GWAS studies produce principal evidence for the association of genetic variants with disease, and provide a jumping-off point for downstream functional analyses. Transcriptomic imputation (TI) allows for the translation of SNPs into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a more broad setting through the use of phenome-wide association studies (PheWAS) in large and erse clinical biobank populations with electronic health record (EHR) phenotypes. Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai Bio Me ™ Biobank and performed PheWAS on over 2000 clinical outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of BMI on AN-GReX clinical associations. Our S-PrediXcan analysis identified 47 genes associated with AN, including what is, to our knowledge, the first genetic association of AN with the Major Histocompatibility Complex (MHC). AN-GReX was associated with autoimmune, anthropometric, metabolic, psychiatric and gastrointestinal diagnoses in our biobank cohort, as well as measures of anthropometry, substance use, and pain score. Our analyses reveal that AN-GReX associations with measures of weight and substance use are modified by BMI, and indicate potential avenues of functional mechanism to investigate further.
Publisher: Cold Spring Harbor Laboratory
Date: 16-04-2021
DOI: 10.1101/2021.04.16.21251163
Abstract: Studying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools. To examine the genetic architecture of AAO and PAO and their association with BD disease characteristics. Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication s le (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts. Earlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. AAO and PAO are associated with indicators of BD severity. In iduals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses. In the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2023
Publisher: Research Square Platform LLC
Date: 20-02-2023
DOI: 10.21203/RS.3.RS-2556941/V1
Abstract: Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) within ~ 4 500 in iduals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores of antidepressant and lithium response for in iduals with MDD, and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1 778 ECT-treated MDD cases, nearly all (94%) used antidepressants before first ECT, and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We found that TRD cases tend to have lower genetic load of antidepressant response than non-TRD, although the difference was not significant furthermore, TRD cases had significantly higher genetic load of lithium response (OR = 1.10–1.12 under different definitions). The results support evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.JPSYCHIRES.2019.03.001
Abstract: In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p < 0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2021
Publisher: Cold Spring Harbor Laboratory
Date: 07-10-2021
DOI: 10.1101/2021.10.04.21264526
Abstract: Longitudinal weight trajectories may reflect in idual health status. We examined the genetic aetiology and clinical consequences of adult weight trajectories in males and females leveraging genetic and phenotypic data in the electronic health records (EHR) of the Bio Me ™ Biobank. We constructed four longitudinal weight trajectories using annual EHR-recorded weights (stable weight, weight gain, weight loss, or weight cycle) (n=21,487). After validating the accuracy of the trajectories (n=100), we conducted a hypothesis-free phenome-wide association study (PheWAS), including sex-stratified PheWAS, to identify diseases associated with each weight trajectory. We then performed a hypothesis-driven polygenic risk score (PRS) analysis on these weight trajectories, focusing on anorexia nervosa (AN) and depression—both commonly associated with weight changes. Weight trajectory classification was highly accurate (accuracy, sensitivity, and specificity 97% for all four trajectories). Hypothesis-free PheWAS analyses identified a significant association between depression and weight cycle (OR=1.4, p≤7.7×10 −16 ) after Bonferroni correction, but not with weight gain or loss. Compared to other weight trajectories, we also observed a significant association of osteoporosis-related phecodes with weight loss in females only (OR female =1.4, p female ≤ 1.4×10 −7 , OR male =0.8, p male ≥ 0.18). AN-PRS was positively associated with weight loss trajectory among in iduals without eating disorder diagnoses (OR top vs. bottom 10% PRS =1.95, p=0.00035). Consistent effect direction was observed across three ancestry groups. The AN-PRS-weight loss association was not attenuated by obesity-PRS (OR top vs. bottom 10% PRS =1.94). Adult weight trajectory is associated with disease both phenotypically and genetically. Our PheWAS reveals unique relationships between diseases and weight trajectory patterns, including the association of depression and weight cycle trajectory in both males and females, and osteoporosis-weight loss trajectory association in females only. In addition, our PRS analysis suggests that adults with higher AN genetic risk are more likely to have a weight loss trajectory, and this association may be independent of BMI/obesity-related genetic pathways. Klarman Family Foundation, NIMH. We used PubMed and medRxiv to search for phenome-wide association studies (PheWAS) of BMI/weight that have been published and/or are currently in preprint. For the weight PheWAS, we used search terms: “(phewas[tiab] OR phenome wide[tiab]) AND (weight[tiab] OR BMI[tiab] OR body mass index[tiab])” on PubMed, and “phewas weight”, “phewas BMI”, “phewas body mass index”, “phenome weight”, “phenome BMI”, or “phenome body mass index” for abstract or title search on medRxiv (up to March 17, 2021). The literature search identified 45 studies in total. From title screening, 13 of the studies were further reviewed, and 5 studies were ultimately included as relevant evidence of PheWAS on weight or BMI. These five PheWAS included four studies of adult populations of European ancestry, and one study conducted in children (ALSPAC). The weight-related exposure variables used in these studies were genetic variants of the obesity-associated FTO gene, BMI-associated SNPs, BMI PRS, BMI value, and obesity status. Through using BMI/obesity-related exposures, these published PheWAS identified comorbidities associated with obesity, including type 2 diabetes, sleep apnea, hypertension, edema, liver disease, asthma, bronchitis, and earlier age of puberty in at least two of the PheWAS. The childhood PheWAS found positive associations of BMI PRS with multiple biomarkers, including leptin, C-reactive protein, IL6, triglyceride, very low-density lipoprotein, and a negative association with high density lipoprotein. One BMI PheWAS published in 2020 observed that hyperlipidemia and gastroesophageal reflux disease were only significantly associated with BMI on a phenotypic level, but not on a genetic level (e.g., BMI or obesity SNPs), likely due to the small genetic effect of single genetic variants. Regarding the impact of anorexia nervosa (AN) and depression genetic risk on weight trajectory, we searched “anorexia nervosa[title] AND (weight[title] OR BMI[title] OR body mass index[title]) AND (genetic[tiab])” or “depression[title] AND (weight[title] OR BMI[title] OR body mass index[title]) AND (genetic[tiab])” on PubMed, and “anorexia polygenic weight” or “anorexia polygenic BMI” or “anorexia polygenic body mass index” or “depression polygenic weight” or “depression BMI” or “depression body mass index” for abstract or title search on medRxiv (up to March 17, 2021). The literature search identified 36 studies in total, and 21 were further reviewed through the title screening. No studies were identified that examined the effect of depression genetic risk on BMI or weight, and only two were included as relevant evidence of AN genetic risk on BMI and weight. Of these two studies, one was cross-sectional in a small adult s le (age 18-59, n=380), and the other was longitudinal in a children/young adult population in the ALSPAC cohort (age 10-24, n=8,654). BMI PRS was found to be associated with lower BMI cross-sectionally, and with weight loss over time only in females. In this study, we create a novel inflection-point based method to classify longitudinal weight trajectory using weights recorded in the EHR in a hospital-based biobank (Mount Sinai Bio Me ™ Biobank), with an accuracy of 98% or higher through our validation study (n=100). With this validated phenotype of weight pattern over time (i.e., weight trajectory), our PheWAS analysis afforded us the opportunity to examine comorbidity across the weight spectrum and across time. We identified 143 diseases associated with weight cycle (e.g., depression, anemias, renal failure),13 diseases positively associated with weight gain trajectory (e.g., obesity, obstructive sleep apnea, edema), and 36 with weight loss (e.g., protein-calorie malnutrition, gastrointestinal complication, end stage renal disease), after Bonferroni correction, using 5% as the cutoff for clinically relevant weight change. All diseases were negatively associated with a stable weight trajectory. Furthermore, we performed, to our knowledge, the first sex-stratified PheWAS related to weight trajectory, and identified eight sex-stratified associations with weight gain (e.g., obstructive sleep apnea), eight with weight loss (e.g., osteoporosis), and ten with weight cycle (e.g., vitamin B-complex deficiencies). On a genetic level, our study fills in the gap of the impact of AN genetic risk on longitudinal weight changes in the adult population. Unlike the finding in adolescents in the ALSPAC study, which found an AN-PRS-weight loss trajectory association only in females, we found an association of higher AN genetic risk with weight loss trajectory in both men and women, with consistent effect direction observed across in iduals with European, African, and Hispanic ancestry in the Bio Me ™ Biobank. Additionally, this association of AN genetics with weight loss was independent of the influence of obesity/BMI related genetic variants on weight. PheWAS is an excellent tool for exploring comorbidities associated across the weight spectrum. Our PheWAS findings identify diseases with different weight patterns (e.g., depression and weight cycle), which may reflect characteristics of these diseases, including age of onset, progression pattern, severity, and chronicity (e.g., the episodic nature of depression with the weight cycle pattern). In addition, our sex-stratified PheWAS implicates the important role of sex in weight regulation in the presence of disease. Certain sub-populations may be at greater risk of weight loss in some disease states (e.g., women with osteoporosis) and may need targeted treatment to address nutritional needs and to prevent further weight loss. Our study also suggests that people who have high AN genetic risk are at greater risk of displaying a weight loss trajectory during adulthood. However, given the limited amount of variation in the outcome of interest (e.g., weight loss) explained by the AN-PRS, the PRS may have to be jointly modeled with other risk factors to predict weight loss more accurately, or to identify subgroups at risk of weight loss. In addition, given our finding that the effect of AN genetics on weight loss was minimally affected by the obesity-related genetics, and the previously reported low genetic correlation of −0.22 between AN and obesity in the 2019 AN GWAS, this may indicate that AN- and obesity-related weight changes might have unique genetic underpinnings. Future studies that assess the pathway-specific genetic risk on weight pattern will further our understanding of the genetic architecture of longitudinal weight trajectory.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2021
DOI: 10.1038/S41398-021-01702-2
Abstract: Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between in iduals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi + Gen www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2013
DOI: 10.1038/MP.2013.37
No related grants have been discovered for Mikael Landén.