Smoller Lab at PNGU


A Quarter Century of Progress in Psychiatric Genetics

Smoller JW - Harvard Review of Psychiatry. doi: 10.1097/HRP.0000000000000180

No abstract available.

Psychiatric Genomics: An Update and an Agenda

Sullivan PF, Agrawal A, Bulik CM, Andreassen OA, Børglum AD, Breen G, Cichon S, Edenberg HJ, Faraone SV, Gelernter J, Mathews CA, Nievergelt CM, Smoller JW, O'Donovan MC; Psychiatric Genomics Consortium - The American Journal of Psychiatry. doi: 10.1176/appi.ajp.2017.17030283

The Psychiatric Genomics Consortium (PGC) is the largest consortium in the history of psychiatry. This global effort is dedicated to rapid progress and open science, and in the past decade it has delivered an increasing flow of new knowledge about the fundamental basis of common psychiatric disorders. The PGC has recently commenced a program of research designed to deliver "actionable" findings-genomic results that 1) reveal fundamental biology, 2) inform clinical practice, and 3) deliver new therapeutic targets. The central idea of the PGC is to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights. The emerging findings suggest that we are entering a phase of accelerated genetic discovery for multiple psychiatric disorders. These findings are likely to elucidate the genetic portions of these truly complex traits, and this knowledge can then be mined for its relevance for improved therapeutics and its impact on psychiatric practice within a precision medicine framework. [AJP at 175: Remembering Our Past As We Envision Our Future November 1946: The Genetic Theory of Schizophrenia Franz Kallmann's influential twin study of schizophrenia in 691 twin pairs was the largest in the field for nearly four decades. (Am J Psychiatry 1946; 103:309-322 )].

Genomewide association studies of suicide attempts in US soldiers

Stein MB, Ware EB, Mitchell C, Chen CY, Borja S, Cai T, Dempsey CL, Fullerton CS, Gelernter J, Heeringa SG, Jain S, Kessler RC, Naifeh JA, Nock MK, Ripke S, Sun X, Beckham JC, Kimbrel NA; VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Workgroup, Ursano RJ, Smoller JW - American Journal of Medical Genetics Part B Neuropsychiatric Genetics. doi: 10.1002/ajmg.b.32594

Suicide is a global public health problem with particular resonance for the US military. Genetic risk factors for suicidality are of interest as indicators of susceptibility and potential targets for intervention. We utilized population-based nonclinical cohorts of US military personnel (discovery: N = 473 cases and N = 9778 control subjects; replication: N = 135 cases and N = 6879 control subjects) and a clinical case-control sample of recent suicide attempters (N = 51 cases and N = 112 control subjects) to conduct GWAS of suicide attempts (SA). Genomewide association was evaluated within each ancestral group (European-, African-, Latino-American) and study using logistic regression models. Meta-analysis of the European ancestry discovery samples revealed a genomewide significant locus in association with SA near MRAP2 (melanocortin 2 receptor accessory protein 2) and CEP162 (centrosomal protein 162); 12 genomewide significant SNPs in the region; peak SNP rs12524136-T, OR = 2.88, p = 5.24E-10. These findings were not replicated in the European ancestry subsamples of the replication or suicide attempters samples. However, the association of the peak SNP remained significant in a meta-analysis of all studies and ancestral subgroups (OR = 2.18, 95%CI 1.70, 2.80). Polygenic risk score (PRS) analyses showed some association of SA with bipolar disorder. The association with SNPs encompassing MRAP2, a gene expressed in brain and adrenal cortex and involved in neural control of energy homeostasis, points to this locus as a plausible susceptibility gene for suicidality that should be further studied. Larger sample sizes will be needed to confirm and extend these findings.

The use of electronic health records for psychiatric phenotyping and genomics

Smoller JW - American Journal of Medical Genetics Part B Neuropsychiatric Genetics. doi: 10.1002/ajmg.b.32548

The widespread adoption of electronic health record (EHRs) in healthcare systems has created a vast and continuously growing resource of clinical data and provides new opportunities for population-based research. In particular, the linking of EHRs to biospecimens and genomic data in biobanks may help address what has become a rate-limiting study for genetic research: the need for large sample sizes. The principal roadblock to capitalizing on these resources is the need to establish the validity of phenotypes extracted from the EHR. For psychiatric genetic research, this represents a particular challenge given that diagnosis is based on patient reports and clinician observations that may not be well-captured in billing codes or narrative records. This review addresses the opportunities and pitfalls in EHR-based phenotyping with a focus on their application to psychiatric genetic research. A growing number of studies have demonstrated that diagnostic algorithms with high positive predictive value can be derived from EHRs, especially when structured data are supplemented by text mining approaches. Such algorithms enable semi-automated phenotyping for large-scale case-control studies. In addition, the scale and scope of EHR databases have been used successfully to identify phenotypic subgroups and derive algorithms for longitudinal risk prediction. EHR-based genomics are particularly well-suited to rapid look-up replication of putative risk genes, studies of pleiotropy (phenomewide association studies or PheWAS), investigations of genetic networks and overlap across the phenome, and pharmacogenomic research. EHR phenotyping has been relatively under-utilized in psychiatric genomic research but may become a key component of efforts to advance precision psychiatry.

Heritability analysis with repeat measurements and its application to resting-state functional connectivity

Ge T, Holmes AJ, Buckner RL, Smoller JW, Sabuncu MR - Proceedings of the National Academy of Sciences of the United States of America. doi: 10.1073/pnas.1700765114

Heritability, defined as the proportion of phenotypic variation attributable to genetic variation, provides important information about the genetic basis of a trait. Existing heritability analysis methods do not discriminate between stable effects (e.g., due to the subject's unique environment) and transient effects, such as measurement error. This can lead to misleading assessments, particularly when comparing the heritability of traits that exhibit different levels of reliability. Here, we present a linear mixed effects model to conduct heritability analyses that explicitly accounts for intrasubject fluctuations (e.g., due to measurement noise or biological transients) using repeat measurements. We apply the proposed strategy to the analysis of resting-state fMRI measurements-a prototypic data modality that exhibits variable levels of test-retest reliability across space. Our results reveal that the stable components of functional connectivity within and across well-established large-scale brain networks can be considerably heritable. Furthermore, we demonstrate that dissociating intra- and intersubject variation can reveal genetic influence on a phenotype that is not fully captured by conventional heritability analyses.

Phenome-wide heritability analysis of the UK Biobank

Ge T, Chen CY, Neale BM, Sabuncu MR, Smoller JW - Public Library of Science Genetics. doi: 10.1371/journal.pgen.1006711

Heritability estimation provides important information about the relative contribution of genetic and environmental factors to phenotypic variation, and provides an upper bound for the utility of genetic risk prediction models. Recent technological and statistical advances have enabled the estimation of additive heritability attributable to common genetic variants (SNP heritability) across a broad phenotypic spectrum. Here, we present a computationally and memory efficient heritability estimation method that can handle large sample sizes, and report the SNP heritability for 551 complex traits derived from the interim data release (152,736 subjects) of the large-scale, population-based UK Biobank, comprising both quantitative phenotypes and disease codes. We demonstrate that common genetic variation contributes to a broad array of quantitative traits and human diseases in the UK population, and identify phenotypes whose heritability is moderated by age (e.g., a majority of physical measures including height and body mass index), sex (e.g., blood pressure related traits) and socioeconomic status (education). Our study represents the first comprehensive phenome-wide heritability analysis in the UK Biobank, and underscores the importance of considering population characteristics in interpreting heritability.

Predicting Suicidal Behavior From Longitudinal Electronic Health Records

Barak-Corren Y, Castro VM, Javitt S, Hoffnagle AG, Dai Y, Perlis RH, Nock MK, Smoller JW, Reis BY - The American Journal of Psychiatry. doi: 10.1176/appi.ajp.2016.16010077

OBJECTIVE: The purpose of this article was to determine whether longitudinal historical data, commonly available in electronic health record (EHR) systems, can be used to predict patients' future risk of suicidal behavior.

METHOD: Bayesian models were developed using a retrospective cohort approach. EHR data from a large health care database spanning 15 years (1998-2012) of inpatient and outpatient visits were used to predict future documented suicidal behavior (i.e., suicide attempt or death). Patients with three or more visits (N=1,728,549) were included. ICD-9-based case definition for suicidal behavior was derived by expert clinician consensus review of 2,700 narrative EHR notes (from 520 patients), supplemented by state death certificates. Model performance was evaluated retrospectively using an independent testing set.

RESULTS: Among the study population, 1.2% (N=20,246) met the case definition for suicidal behavior. The model achieved sensitive (33%-45% sensitivity), specific (90%-95% specificity), and early (3-4 years in advance on average) prediction of patients' future suicidal behavior. The strongest predictors identified by the model included both well-known (e.g., substance abuse and psychiatric disorders) and less conventional (e.g., certain injuries and chronic conditions) risk factors, indicating that a data-driven approach can yield more comprehensive risk profiles.

CONCLUSIONS: Longitudinal EHR data, commonly available in clinical settings, can be useful for predicting future risk of suicidal behavior. This modeling approach could serve as an early warning system to help clinicians identify high-risk patients for further screening. By analyzing the full phenotypic breadth of the EHR, computerized risk screening approaches may enhance prediction beyond what is feasible for individual clinicians.

Genome-wide association study of generalized anxiety symptoms in the Hispanic Community Health Study/Study of Latinos

Dunn EC, Sofer T, Gallo LC, Gogarten SM, Kerr KF, Chen CY, Stein MB, Ursano RJ, Guo X, Jia Y, Qi Q, Rotter JI, Argos M, Cai J, Penedo FJ, Perreira K, Wassertheil-Smoller S, Smoller JW - American Journal of Medical Genetics Part B Neuropsychiatric Genetics. doi: 10.1002/ajmg.b.32448

Although generalized anxiety disorder (GAD) is heritable and aggregates in families, no genomic loci associated with GAD have been reported. We aimed to discover potential loci by conducting a genome-wide analysis of GAD symptoms in a large, population-based sample of Hispanic/Latino adults. Data came from 12,282 participants (aged 18-74) in the Hispanic Community Health Study/Study of Latinos. Using a shortened Spielberger Trait Anxiety measure, we analyzed the following: (i) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V; and (ii) a total trait anxiety score based on summing responses to all ten items. We first calculated the heritability due to common variants (h2SNP ) and then conducted a genome-wide association study (GWAS) of GAD symptoms. Replication was attempted in three independent Hispanic cohorts (Multi-Ethnic Study of Atherosclerosis, Women's Health Initiative, Army STARRS). The GAD symptoms score showed evidence of modest heritability (7.2%; P = 0.03), while the total trait anxiety score did not (4.97%; P = 0.20). One genotyped SNP (rs78602344) intronic to thrombospondin 2 (THBS2) was nominally associated (P = 5.28 × 10-8 ) in the primary analysis adjusting for psychiatric medication use and significantly associated with the GAD symptoms score in the analysis excluding medication users (P = 4.18 × 10-8 ). However, meta-analysis of the replication samples did not support this association. Although we identified a genome-wide significant locus in this sample, we were unable to replicate this finding. Evidence for heritability was also only detected for GAD symptoms, and not the trait anxiety measure, suggesting differential genetic influences within the domain of trait anxiety.

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

Charney AW, Ruderfer DM, Stahl EA, Moran JL, Chambert K, Belliveau RA, et. al. - Translational Psychiatry doi: 10.1038/tp.2016.242

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial

Roffman JL, Petruzzi LJ, Tanner AS, Brown HE, Eryilmaz H, Ho NF, Giegold M, Silverstein NJ, Bottiglieri T, Manoach DS, Smoller JW, Henderson DC, Goff DC - Molecular Psychiatry doi: 10.1038/mp.2017.41

Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials., NCT01091506.


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