Depression and obesity: evidence of shared biological mechanisms

Milaneschi, Yuri; Simmons, W. Kyle; Rossum, Elisabeth F.C. van; Penninx, Brenda W.J.H.

doi:10.1038/s41380-018-0017-5

Cited by 696 publications

(574 citation statements)

References 184 publications

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“…In addition, the pleiotropic risk loci were enriched among genes previously associated with neuroticism (corrected enrichment p= 5.28x10 -6 ; GRIK3, CTNND1,DRD2,RGS6,RBFOX1,ZNF804A,L3MBTL2,CHADL,RANGAP1,RSRC1,GRM3), cognitive ability (corrected p= 7.15x10 -5 ; PTPRF, NEGR1, ELOVL3, SORCS3, DCC, CACNA1I), and night sleep phenotypes (corrected p= 1.86x10 -2 ; PBX1, NPAS3, RGS6,GRIN2A,MYO18A,TIAF1,CNTN4,PPP2R2B,TENM2,CSMD1). We also found significant enrichment of pleiotropic risk genes in multiple measures of body mass index (BMI), supporting previous studies suggesting a shared etiologic basis between a range of neuropsychiatric disorders and obesity (Hartwig et al, 2016;Lopresti and Drummond, 2013;Milaneschi et al, 2018)…”

Section: Relationship Between Cross-disorder Genetic Risk and Other Bsupporting

confidence: 89%

Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

Ph¹,

Anttila²,

Won³

et al. 2019

Preprint

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Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction. Genetic correlations among eight neuropsychiatric disorders indicate three genetic factors.After standardized and uniform quality control, additive logistic regression analyses were performed on individual disorders (Methods). A total of 6,786,994 SNPs were common across all datasets and were retained for further study. Using the summary statistics of these SNPs, we first estimated pairwise genetic correlations among the eight disorders using linkage disequilibrium (LD) score regression analyses (Bulik-Sullivan et al., 2015a) (Methods; Fig. 1a; Supplementary Table 2). The results were broadly concordant with previous estimates (Brainstorm Consortium, 2018; Cross-Disorder Group of the Psychiatric Genomics Consoritum, 2013). The genetic correlation was highest between SCZ and BIP (rg = 0.70 ±0.02), followed by OCD and AN (rg = 0.50 ±0.12). Interestingly, based on genome-wide genetic correlations, MD was closely correlated with ASD (rg=0.45 ±0.04) and ADHD (rg=0.44 ±0.03), two childhood-onset disorders. Despite variation in magnitude, significant genetic correlations were apparent for most pairs of disorders, suggesting a complex, higher-order genetic structure underlying psychopathology ( Fig. 1b).We modeled the genome-wide joint architecture of the eight neuropsychiatric disorders using an exploratory factor analysis (EFA) (Gorsuch, 1988), followed by genomic structural equation modeling (SEM) (Grotzinger et al., 2018) (Methods). EFA identified three correlated factors, which together explained 51% of the genetic variation in the eight neuropsychiatric disorders ( Supplementary Table 3). The first factor consisted primarily of disorders characterized by compulsive behaviors, specifically AN, OCD, and, more weakly, TS. The second factor was characterized by mood and psychotic disorders (MD, BIP, and SCZ), and the third factor by three early-onset neurodeve...

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Section: Relationship Between Cross-disorder Genetic Risk and Other Bsupporting

confidence: 89%

Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

Ph¹,

Anttila²,

Won³

et al. 2019

Preprint

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“…Looking at specific QTL, we identified the genes Insig2 and Ksr2 on the highest point in the region for the class Mollicutes (chr1:121,315,223, LOD = 7.002) and the order Bacteroidales (chr5:117,733,508, LOD = 7.203) respectively. INSIG2 plays a central role in the pathway by which the circadian clock regulates liver lipid metabolism and Ksr2 has been implicated in being associated with BMI and severe early-onset obesity through large scale GWAS studies [Milaneschi et al 2019].…”

Section: Qtl Mappingmentioning

confidence: 99%

High-resolution QTL mapping with Diversity Outbred mice identifies genetic variants that impact gut microbiome composition

Schlamp

Zhang

Cosgrove

et al. 2019

Preprint

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The composition of the gut microbiome is impacted by a complex array of factors, from nutrient composition and availability, to physical factors like temperature, pH and flow rate, as well as interactions among the members of the microbial community. Many of these factors are affected by the host, raising the question of how host genetic variation impacts microbiome composition. Human studies confirm a role for host genetics, but opinions vary on just how important is host genetic variation in determining gut microbiome composition. The mouse model, by allowing far better control of genetics, nutrition, and other environmental factors, has provided an excellent opportunity to extend this work, and the Diversity Outbred (DO) mice in particular present a chance for mapping host genetic variants that influence specific attributes of microbiome composition. Here we apply 16s sequencing to fecal samples of 247 DO mice and perform QTL mapping on microbial abundances. In addition to finding a number of novel associations, the concordance with heritabilities and associations with both human and mouse studies was striking, including the phylum Tenericutes, family Ruminococcaceae, as well as Staphylococcus and Turicibacter.

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“…Yet, intervention studies showed that a plant-based vegan diet compared to a conventional omnivorous diet reduced anxiety and depression or emotional distress 19–22 , proposing that restricting animal-based products per se may not affect mental health, but rather exert beneficial effects. Notably, we observed that different personality traits and BMI predicted depressive symptom score, which hints towards shared neurobiological mechanisms with obesity 23,25 . These shared mechanisms might help to explain previous inconsistent findings of a proposed link between restrictive diets and depression: certain personality traits may increase the probability to restrict certain food groups from diet, such as openness and conscientiousness 59 .…”

Section: Discussionmentioning

confidence: 54%

“…In addition, both weight gain and weight loss may relate to depressive symptoms 23 , and obesity and depression are assumed to share not only certain symptoms but also genetic pathways and personality traits, in particular neuroticism (reviewed in 24 ). For example, studies showed that higher neuroticism and lower conscientiousness correlate with a higher BMI and more depressive symptoms 25,26 . Moreover, differences in personality traits and demographic factors such as age, sex and education have also been linked to more or less restrictive lifestyle habits, including diet 27–29 .…”

Section: Introductionmentioning

confidence: 99%

Lower intake of animal-based products links to improved weight status, independent of depressive symptoms and personality in the general population

Medawar

Enzenbach²,

Röhr

et al. 2020

Preprint

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Depression and obesity: evidence of shared biological mechanisms

Cited by 696 publications

References 184 publications

Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

High-resolution QTL mapping with Diversity Outbred mice identifies genetic variants that impact gut microbiome composition

Lower intake of animal-based products links to improved weight status, independent of depressive symptoms and personality in the general population

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