Susan L Santangelo

Maine Medical Center Research Institute | MMCRI · Center for Psychiatric Research

Purpose To investigate the enduring disparities in adverse COVID‐19 events between urban and rural communities in the United States, focusing on the effects of SARS‐CoV‐2 vaccination and therapeutic advances on patient outcomes. Methods Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined...

Background The COVID-19 pandemic has demonstrated the need for efficient and comprehensive, simultaneous assessment of multiple combined novel therapies for viral infection across the range of illness severity. Randomized Controlled Trials (RCT) are the gold standard by which efficacy of therapeutic agents is demonstrated. However, they rarely are...

Background While COVID-19 vaccines reduce adverse outcomes, post-vaccination SARS-CoV-2 infection remains problematic. We sought to identify community factors impacting risk for breakthrough infections (BTI) among fully vaccinated persons by rurality. Methods We conducted a retrospective cohort study of US adults sampled between January 1 and Dece...

There is converging evidence that abnormal thalamocortical interactions contribute to attention deficits and sensory sensitivities in autism spectrum disorder (ASD). However, previous functional MRI studies of thalamocortical connectivity in ASD have produced inconsistent findings in terms of both the direction (hyper vs. hypoconnectivity) and loca...

The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the ge...

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10−6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRN...

Background: It is unclear whether vitamin D benefits inpatients with COVID-19. Objective: To examine the relationship between vitamin D and COVID-19 outcomes. Design: Cohort study. Setting: National COVID Cohort Collaborative (N3C) database. Patients: 158,835 patients with confirmed COVID-19 and a sub-cohort with severe disease (n = 81,381) hospita...

Objectives: Although the World Health Organization (WHO) Clinical Progression Scale for COVID-19 is useful in prospective clinical trials, it cannot be effectively used with retrospective Electronic Health Record (EHR) datasets. Modifying the existing WHO Clinical Progression Scale, we developed an ordinal severity scale (OS) and assessed its usef...

Purpose: Rural communities are among the most underserved and resource-scarce populations in the United States. However, there are limited data on COVID-19 outcomes in rural America. This study aims to compare hospitalization rates and inpatient mortality among SARS-CoV-2-infected persons stratified by residential rurality. Methods: This retrosp...

Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 1 in 36 children in the united states, imposing enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identified de novo copy number variants (CNVs) and point mutations that contribute significantly to the gen...

Nucleolin (NCL/C23; OMIM: 164035) is a major nucleolar protein that plays a critical role in multiple processes, including ribosome assembly and maturation, chromatin decondensation, and pre-rRNA transcription. Due to its diverse functions, nucleolin has frequently been implicated in pathological processes, including cancer and viral infection. We...

Background A major challenge to identifying effective treatments for COVID-19 has been the conflicting results offered by small, often underpowered clinical trials. The World Health Organization (WHO) Ordinal Scale (OS) has been used to measure clinical improvement among clinical trial participants and has the benefit of measuring effect across the...

IMPORTANCE: Rural communities are among the most underserved and resource-scarce populations in the United States (US), yet there are limited data on COVID-19 mortality in rural America. Furthermore, rural data are rarely centralized, precluding comparability across urban and rural regions. OBJECTIVE: The purpose of this study is to assess hospital...

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptiv...

Background: Fear of autism has led to a decline in childhood-immunization uptake and to a resurgence of preventable infectious diseases. Identifying characteristics of parents who believe in a causal role of vaccines for autism spectrum disorder (ASD) in their child may help targeting educational activities and improve adherence to the immunizatio...

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 analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity...

In 2015, two strong earthquakes, as well as continuous, high magnitude aftershocks, struck Nepal. Phulpingdanda village was greatly impacted due to its lack of infrastructure and environmental remoteness. Adults from sampled households were surveyed 1-year later to examine the association between earthquake exposures and indicators of depression, p...

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/hypera...

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptiv...

Background Mental health issues can reach epidemic proportions in developed countries after natural disasters, but research is needed to better understand the impact on children and adolescents in developing nations. Methods A cross-sectional study was performed to examine the relationship between earthquake exposures and depression, PTSD, and res...

We present the largest exome sequencing study to date focused on rare variation in autism spectrum disorder (ASD) (n=35,584). Integrating de novo and case-control variation with an enhanced Bayesian framework incorporating evolutionary constraint against mutation, we implicate 99 genes in ASD risk at a false discovery rate (FDR) ≤ 0.1. Of these 99...

Psychiatric hospitalization of children with autism spectrum disorder (ASD) is relatively common and occurs at a higher rate than in non-ASD youth. This study compared changes in the severity of serious problem behaviors in 350 youth with ASD enrolled in the autism inpatient collection during and after hospitalization in six specialized child psych...

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from...

Brainstorming diseases Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric...

Autism Spectrum Disorder (ASD) is thought to reflect disrupted development of brain connectivity characterized by white matter abnormalities and dyscoordination of activity across brain regions that give rise to core features. But there is little consensus about the nature, timing and location of white matter abnormalities as quantified with diffus...

Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample s...

Background Epidemiologic evidence suggests that periconceptional maternal folate intake is associated with decreased risk for autism spectrum disorder (ASD), but the biochemical underpinnings of this relationship and direct maternal folate measurement have not been reported. Objective To examine the association between first trimester in utero mat...

The theme of this volume that psychiatry and neuropsychology be systematically aligned with the neurophenotype approach in order to facilitate a systems-level understanding of brain–behavior relationships is reiterated across chapters. This chapter outlines a few conceptual and programmatic adjustments that these disciplines must undertake in order...

This chapter provides a critical appraisal of the concept of a circuit-centered neurophenotype that is conceptualized within a genome-to-phenome framework. Representing many of the kinds of variables that complicate this model are a few select ones that are sampled in this chapter. They include the following: (a) The problem of minimal circuit defi...

This introductory chapter provides a summary description of key developments in the neurosciences and biomedical sciences that have compelled the topic of the volume—neural and cognitive markers. The emergence of “omics” disciplines is described—where large or complex data sets are deciphered with bioinformatics methods in a systems biology framewo...

The developments of phenomics, connectomics, and Research Domain Criteria (RDoC) set forth in the introductory chapter are given expanded review in this chapter. The strategy of phenomics is laid out with particular reference to the influences of genetic studies—both candidate gene and genome-wide association studies. How current developments in ge...

The interest in ‘biomarkers’ seen across a spectrum of biomedical disciplines reflects the rise of molecular biology and genetics. A host of ‘omics’ disciplines in addition to genomics, marked by multidimensional data and complex analyses, and enabled by bioinformatics, have pushed the trajectory of biomarker development even further. They have als...

Background Individuals severely affected by autism spectrum disorder (ASD), including those with intellectual disability, expressive language impairment, and/or self-injurious behavior (SIB), are underrepresented in the ASD literature and extant collections of phenotypic and biological data. An understanding of ASD’s etiology and subtypes can only...

Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate line...

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomic...

Importance Although autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of subclinical autistic traits in nonclinical samples are poorly understood.Objective To examine the familiality of Social Responsiveness Scale (SRS) scores of individuals with and without ASD.Design, Setting, and Participants We performed a nest...

Background: Presented on behalf of the Psychiatric Genomics Consortium: Autism Spectrum Disorder Working Group. Although copy number variants and rare mutations have been demonstrated to increase risk for ASD, empirical evidence supporting a large role for inherited common variants as risk factors for ASD risk is still lacking. Objectives: In ord...

Background: In February 2013, the cross-disorder group (CDG) of the Psychiatric Genomics Consortium (PGC), published the largest genetic study of mental illness ever done. Scanning the genomes of over 33,000 patients and nearly 28,000 controls, we investigated the possibility that common genetic variants might affect susceptibility to five psychi...

Nepal is one of the poorest countries in the world and almost half the children in the country suffer from malnutrition. Awareness and knowledge about autism are almost nonexistent. A small study showed that the mean age of first symptom recognition in Nepal is around 30 months of age. After recognition, there is a delay of about 30 months before d...

Autism spectrum disorders (ASD) are much more common in males than in females. Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association...

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, m...

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, m...

Our goal in this study was to determine whether maternal fat intake before or during pregnancy was associated with risk of autism spectrum disorder (ASD) in the offspring. Our primary analysis included 317 mothers who reported a child with ASD and 17,728 comparison mothers from the Nurses' Health Study II (index births in 1991-2007). Dietary inform...

Background: Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention defic...

Background Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specifi c variants underlying genetic eff ects shared between the fi ve disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention defi...

BACKGROUND: Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention defici...

The true prevalence of HIV and other sexually transmitted diseases among street children in Nepal is virtually unknown while information on related behavioural risk factors in this population is non-existent. The risk of HIV infection among street children and adolescents may be especially high due to their marginalized social and economic conditio...

An increasing number of women are utilizing fertility treatments, but little is known about their relation to autism spectrum disorders (ASD). To determine the association between maternal fertility therapy use and risk of having a child with ASD, we conducted a nested case-control study within the Nurses' Health Study II (n = 116,430). Maternally...

Background: The hope and promise of genome-wide association studies to yield common variants for autism remains largely unfulfilled. Under the assumption that the extant autism GWA studies suffer from inadequate power, the Autism Working Group of the Psychiatric GWAS Consortium (PGC) has assembled a large sample of autism spectrum disorder (ASD) tr...

The authors examined pregnancy and obstetric complications in association with autism spectrum disorders (ASD) in children of participants from the Nurses' Health Study II, a prospective national cohort with information collected through biennial mailed questionnaires since 1989. Logistic regression was used to obtain crude and adjusted odds ratios...

We investigated the extent to which methodological concerns explicitly addressed by the designers of the World Mental Health Surveys persist in the results that were obtained using the WMH-CIDI instrument. We compared rates of endorsement of mental illness symptoms in the United States (very high) and Nepal (very low) as they were affected by respo...

Background: A wide variety of evidence, using many different behavioral paradigms, indicates a broad role for the involvement of the extracellular signaling-regulated kinases (ERK) pathway in synaptic plasticity and consequently learning and memory. Disruption of neuronal protein synthesis through ERK pathway is the shared point of several essentia...

It is not known whether reproductive factors early in the mother's life influence risk of autism spectrum disorders (ASD). We assessed maternal age at menarche, menstrual cycle characteristics during adolescence, oral contraceptive use prior to first birth, body shape, and body mass index (BMI) in association with ASD using binomial regression in a...

Biological and positional evidence supports the involvement of the GAD1 and distal-less homeobox genes (DLXs) in the etiology of autism. We investigated 42 single nucleotide polymorphisms in these genes as risk factors for autism spectrum disorders (ASD) in a large family-based association study of 715 nuclear families. No single marker showed sign...

This is the first investigation of the relationship between parental age and extreme social-communicative autistic traits in the general population. The parents of 5,246 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) completed the Social and Communication Disorders Checklist (SCDC). The association between parental age and...

Background: For reasons not yet understood, there is a significant sex bias in the prevalence of autism, with a male-to-female ratio of 4:1. Some linkage and candidate gene association studies of ASD have employed a sex-spliting strategy and found genetic effects specific to families with only affected males (Male-only; MO) versus families containi...

Background: The co-occurrence of Autism Spectrum Disorders (ASD) and Tuberous Sclerosis Complex (TSC) has been recognized for many years. TSC involves two genes, TSC1 and TSC2, which function together to inhibit mammalian Target of Rapamycin (mTOR) signaling. mTOR signaling plays an essential role in neural plasticity, and activation of mTOR signal...

Background: An increasing number of women are utilizing fertility treatments, and the safety of these therapies has been studied with regard to a number of perinatal outcomes. However, the relationship between infertility, fertility treatments, and autism spectrum disorders remains understudied. Objectives: To determine whether infertility and us...

Background: Prior reports have documented considerable variability in language abilities among verbal children with ASD (Kjelgaard and Tager-Flusberg, 2001). A variety of measures are used to assess language abilities in school-age children including direct face-to-face assessments with the child, and questionnaires that are completed by the child’...

Autism is a neurodevelopmental disorder which is known to have a strong genetic component and is most likely oligogenic. However, the necessary role of environmental factors has been well documented. Prior research suggests that parental characteristics, such as age and level of education, may be associated with a risk of autism. Parental age has b...

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and phonic tics. The heritability of TS has been well established, yet there is a lack of consensus in genome-wide linkage studies. The purpose of this study was to conduct a genome-wide linkage analysis on a unique, large, high-risk TS Utah pedigree. We examined...

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes...

Electrophysiological traits, indexing schizophrenia endophenotypes, were measured in over 600 members of a genetic isolate in Jiri, Nepal, who are members of a single pedigree. Measured traits include P50 and P300 amplitude and latency, and oscillatory brain activity in the gammaband range (35–45 Hz). The power of induced gammaband activity, as mea...

Over the past 2 years genome-wide association studies have made major contributions to understanding the genetic architecture of many common human diseases. This editorial outlines the development of such studies in psychiatry and highlights the opportunities for advancing understanding of the biological underpinnings and nosological structure of p...

Background: Prior research has indicated that autism spectrum disorder (ASD) is strongly heritable and that there are valuable lessons to be learned by studying family members of individuals with ASD. The Social Responsiveness Scale (SRS), developed by Constantino and colleagues (2000) is a quantitative measure of ASD traits. Constantino and Todd (...

The serotonin transporter gene (5-HTT) plays a crucial role in serotonergic neurotransmission and has been found to be associated, with varying degrees of significance, with many diseases, including autism. Prior association studies of autism have yielded conflicting results regarding the association between two common 5-HTT polymorphisms, the prom...

BACKGROUND: Although susceptibility loci exist for Gilles de la Tourette syndrome (GTS), no causative gene has been identified, perhaps in part because of phenotypic heterogeneity. This study used latent class analyses (LCA) to identify GTS subphenotypes and assess characteristics and heritability of the classes. METHODS: The study included 952 ind...

Background: Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. Methods: As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotyp...