An evolutionary perspective on complex neuropsychiatric disease

McClellan, Jon M.; Zoghbi, Anthony W.; Buxbaum, Joseph D.; Cappi, Carolina; Crowley, James J.; Flint, Jonathan; Grice, Dorothy E.; Gulsuner, Suleyman; Iyegbe, Conrad; Jain, Sanjeev; Kuo, Po-Hsiu; Lattig, Maria Claudia; Passos-Bueno, Maria Rita; Purushottam, Meera; Stein, Dan J.; Sunshine, Anna B.; Susser, Ezra S.; Walsh, Christopher A.; Wootton, Olivia; King, Mary-Claire

doi:10.1016/j.neuron.2023.10.037

Cited by 3 publications

(4 citation statements)

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“…The epidemiology, and semiology, of psychiatric syndromes such as BD1 and OCD are quite similar all over the world. This suggests that there is likely a similar genetic liability, with a shared set of genomic loci influencing these phenotypes across populations (30). Nonetheless, ancestry-related variations in LD patterns, with the true causal variant, as well as diverse environmental interactions, may affect the size of the genetic effect.…”

Section: Discussionmentioning

confidence: 99%

A cross ancestry genetic study of psychiatric disorders from India

Holla,

Mahadevan,

Ganesh

et al. 2024

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Genome-wide association studies across diverse populations may help validate and confirm genetic contributions to risk of disease. We estimated the extent of population stratification as well as the predictive accuracy of polygenic scores (PGS) derived from European samples to a data set from India. We analysed 2685 samples from two data sets, a population neurodevelopmental study (cVEDA) and a hospital-based sample of bipolar affective disorder (BD) and obsessive-compulsive disorder (OCD). Genotyping was conducted using Illumina's Global Screening Array. Population structure was examined with principal component analysis (PCA), uniform manifold approximation and projection (UMAP), support vector machine (SVM) ancestry predictions, and admixture analysis. PGS were calculated from the largest available European discovery GWAS summary statistics for BD, OCD, and externalizing traits using two Bayesian methods that incorporate local linkage disequilibrium structures (PGS-CS-auto) and functional genomic annotations (SBayesRC). Our analyses reveal global and continental PCA overlap with other South Asian populations. Admixture analysis revealed a north-south genetic axis within India (FST 1.6%). The UMAP partially reconstructed the contours of the Indian subcontinent. The Bayesian PGS analyses indicates moderate-to-high predictive power for BD. This was despite the cross-ancestry bias of the discovery GWAS dataset, with the currently available data. However, accuracy for OCD and externalizing traits was much lower. The predictive accuracy was perhaps influenced by the sample size of the discovery GWAS and phenotypic heterogeneity across the syndromes and traits studied. Our study results highlight the accuracy and generalizability of newer PGS models across ancestries. Further research, across diverse populations, would help understand causal mechanisms that contribute to psychiatric syndromes and traits.

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Section: Discussionmentioning

confidence: 99%

A cross ancestry genetic study of psychiatric disorders from India

Holla,

Mahadevan,

Ganesh

et al. 2024

Preprint

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“…For instance, BPD and especially ADHD can take several decades to be diagnosed. The genetics of MDD are very complex with about 180 primary target genes (McClellan et al, 2024), although some genome wide association studies (GWAS) have relied on rather "loose" disease criteria (Cai et al, 2020a(Cai et al, , 2020bFlint, 2023). In addition, comorbidity is not uncommon, and it is not surprising to see overlaps between MDD, GAD, PTSD, SUD, panic disorders, BPD, to name a few (Kupfer et al, 2013;Regier et al, 2013aRegier et al, , 2013b when there are potentially hundreds of symptom combinations that can define MDD.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, comorbidity is not uncommon, and it is not surprising to see overlaps between MDD, GAD, PTSD, SUD, panic disorders, BPD, to name a few (Kupfer et al, 2013;Regier et al, 2013aRegier et al, , 2013b when there are potentially hundreds of symptom combinations that can define MDD. Hence, the diagnosis agreement/overlap of MDD and related diseases, even between experienced clinicians can range from excellent to rather poor, (as low as 15% or less, Regier et al, 2013b;McClellan et al, 2024;Clarke et al, 2013). As pointed out, "Two individuals can meet DSM-5 criteria for MDD without sharing a single symptom" (McClellan et al, 2024).…”

Section: Introductionmentioning

confidence: 99%

“…Hence, the diagnosis agreement/overlap of MDD and related diseases, even between experienced clinicians can range from excellent to rather poor, (as low as 15% or less, Regier et al, 2013b;McClellan et al, 2024;Clarke et al, 2013). As pointed out, "Two individuals can meet DSM-5 criteria for MDD without sharing a single symptom" (McClellan et al, 2024).…”

Section: Introductionmentioning

confidence: 99%

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On serotonin, psychedelics, entactogens and psychoplastogens in depression, anxiety, post-traumatic stress, and related disorders.

Hoyer

2024

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There is controversy about a causal role of serotonin (5-HT) in depression, some arguing that there is no proof for impaired brain 5-HT function in depressed patients. Major depressive disorder comes with multiple endophenotypes; not surprisingly classical antidepressants (tricyclics, MAO inhibitors, SSRIs, SNRIs) are not universally effective. Most antidepressants target the 5-HT system, partially if not exclusively, but treatment-resistant depression (TRD) remains a major issue. The most recent and heavily investigated class of potential rapid acting antidepressant, anxiolytic, and/or anti PTSD drugs, namely psychedelics (psilocybin, LSD, DMT, ayahuasca, etc..) or entactogens (MDMA, ibogaine), all target the 5-HT system, at least in part. Phase II / III clinical trials support psychedelics- and/or MDMA-assisted psychotherapy as a new class of rapid acting treatments for GAD, MDD, TRD, PTSD, and other disorders. Psilocybin and MDMA have FDA breakthrough status for TRD/MDD and PTSD, respectively, whereas LSD just received FDA breakthrough status for GAD. All psychedelics act as 5-HT2A receptor agonists, although LSD, DMT, psilocybin may also target other 5-HT and/or dopamine receptors. Psychedelics produce rapid onset and long-lasting antidepressant effects after one or two administrations. They all promote synaptogenesis and synaptic plasticity. Neuroinflammation plays a major role in anxiety, depression, PTSD. Interestingly, psychedelic-induced 5-HT2A receptor agonism has profound anti-(neuro)inflammatory effects. Altogether, the 5-HT system plays an essential, but not unique role in MDD and related disorders. MDD, TRD and PTSD may be considered as biochemical, neurological and immune conditions, given the emerging role of neuroplasticity and neuroinflammation, which until recently, have been overlooked.

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