Genetic Protective Factors Research Articles

Measuring the Impact of Genetic and Environmental Risk and Protective Factors on Speech, Language, and Communication Development-Evidence from Australia.

Speech and language acquisition is one of the key development indicators of optimal literacy development in infancy and early childhood. Over the last decade there has been increasing interest in the development of theoretical frameworks which underpin the underlying complexity of a child’s language developmental landscapes. This longitudinal study aims to measure the impact of genetic and environmental risk and protective factors on speech, language, and communication development (SLCN) among 5000 infants in Australia. Using robust panel fixed-effects models, the results demonstrate that there are clear and consistent effects of protective factors and SLCN associated with the infant’s family [coefficient (SD) = 0.153, 95% standard error (SE) = 8.76], the in utero environment [coefficient (SD) = 0.055, standard error (SE) = 3.29] and early infant health [coefficient (SD) = 0.074, standard error (SE) = 5.28]. The impact of family and in utero health is dominant at aged 2 to 3 years (relative to 0 to 1 years) across the domains of language and communication and more dominant from birth to 1 years for speech acquisition. In contrast, the evidence for the impact of genetics on SLCN acquisition in infancy, is less clear. The evidence from this study can be used to inform intervention policies.

A comparison of the existential and medical models of addiction

IntroductionAfter developing an existential model of addiction, it became evident that there are major differences between the existential and medical models of addiction.ObjectivesThis research aims to investigate the boundary and overlap between the existential and medical models of addiction.MethodsThe existential model was compared and contrasted with a narrative literature review of the medical model of addiction.ResultsThrough the existential definition being-with-drug, addiction is conceptualised in terms of a relationship with the drug and the impact on one’s sense of self. The medical model focuses on diagnostic criteria, genetic and environmental risk and protective factors, and an underlying neurobiological explanation. In contrast to the prevalent disease model, the existential view maintains that drug addiction is a coping mechanism used to mitigate existential and neurotic anxiety which results from facing or avoiding the existential givens. Phenomenological research supporting existential psychotherapy in addiction is contrasted with the quantitative medical research which forms the basis for current addiction guidelines. A comparison of both models is presented focusing on the issues of coping, choice, responsibility, mandatory treatment, medication, psychotherapy and the therapeutic relationship. The biopsychosocial model is compared to van Deurzen’s modes of existence, which provides the basis for existential psychotherapeutic interventions. Furthermore, existential literature was examined to determine whether an individual can authentically choose to live addicted.ConclusionsBoth models fall short of giving a holistic view of addiction. A combination of models is necessary to address the diversity of issues patients present with.

Association Study of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Polymorphism With Alzheimer Disease in the Taiwanese Population.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are two major alcohol-metabolizing enzymes. Moderate alcohol intake is a protective modified factor in Alzheimer’s disease (AD) while heavy alcohol intake and abstinence increased dementia risk. The associations between Alzheimer’s disease and alcohol-metabolizing genes are uncertain. This study examined the association of AD with seven ADH/ALDH single-nucleotide polymorphisms (SNPs), ADH1C rs2241894, ADH1B rs1229984, ALDH1B1 rs2073478, ALDH2 rs886205, rs4767944, rs4648328, and rs671. We enrolled 157 AD and 168 age- and sex-matched control subjects in pilot study to examine the association of AD with ADH/ALDH SNPs. Reconstructed ALDH2 haplotypes were performed. We measured plasma level of ADH1C and checked the interaction effect of AD–rs2241894 genotype on plasma ADH1C level. In extension study, we further examined 339 AD and 2,504 healthy control from the Taiwan Biobank. In pilot study, we observed that ADH1C rs2241894 TT genotype was negatively associated with AD in a recessive genetic model (OR = 0.25, 95% CI 0.09–0.75, p < 0.0001) in women. A strong linkage disequilibrium was observed among the four examined SNPs of ALDH2. No haplotype was related to AD. The plasma ADH1C level in AD was higher than that in control. After adjusted by age, sex, hypertension, diabetes mellitus, and alcohol, we found a significant interaction effect of AD–rs2241894 genotype on plasma ADH1C level (p = 0.04). This interaction effect was attributable to the association between AD and plasma ADH1C level (β estimate = 366, 95% CI 92.7∼639.4, p = 0.009). The genetic distribution of ADH1C rs2241894 showed strong ethnic heterogeneity, in which the T allele was the minor allele accounting for 28.5% in our study and 23.6% in East Asians, while it was a major allele in Americans, Europeans, and the global populations. No association was discovered between AD and the five SNPs: rs2241894, rs1229984, rs2073478, rs886205, and rs671 in the extension study. In summary, this study revealed a suggestive association between ADH1C rs2241894 and female AD in the pilot study, but failed to confirm this finding in a population database. Further age-matched and large sample size case-control studies are needed before rs2241894 can be interpreted as a protective genetic factor of AD.

Non-genetic risk and protective factors and biomarkers for neurological disorders: a meta-umbrella systematic review of umbrella reviews

BackgroundThe etiologies of chronic neurological diseases, which heavily contribute to global disease burden, remain far from elucidated. Despite available umbrella reviews on single contributing factors or diseases, no study has systematically captured non-purely genetic risk and/or protective factors for chronic neurological diseases.MethodsWe performed a systematic analysis of umbrella reviews (meta-umbrella) published until September 20th, 2018, using broad search terms in MEDLINE, SCOPUS, Web of Science, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature, ProQuest Dissertations & Theses, JBI Database of Systematic Reviews and Implementation Reports, DARE, and PROSPERO. The PRISMA guidelines were followed for this study. Reference lists of the identified umbrella reviews were also screened, and the methodological details were assessed using the AMSTAR tool. For each non-purely genetic factor association, random effects summary effect size, 95% confidence and prediction intervals, and significance and heterogeneity levels facilitated the assessment of the credibility of the epidemiological evidence identified.ResultsWe identified 2797 potentially relevant reviews, and 14 umbrella reviews (203 unique meta-analyses) were eligible. The median number of primary studies per meta-analysis was 7 (interquartile range (IQR) 7) and that of participants was 8873 (IQR 36,394). The search yielded 115 distinctly named non-genetic risk and protective factors with a significant association, with various strengths of evidence. Mediterranean diet was associated with lower risk of dementia, Alzheimer disease (AD), cognitive impairment, stroke, and neurodegenerative diseases in general. In Parkinson disease (PD) and AD/dementia, coffee consumption, and physical activity were protective factors. Low serum uric acid levels were associated with increased risk of PD. Smoking was associated with elevated risk of multiple sclerosis and dementia but lower risk of PD, while hypertension was associated with lower risk of PD but higher risk of dementia. Chronic occupational exposure to lead was associated with higher risk of amyotrophic lateral sclerosis. Late-life depression was associated with higher risk of AD and any form of dementia.ConclusionsWe identified several non-genetic risk and protective factors for various neurological diseases relevant to preventive clinical neurology, health policy, and lifestyle counseling. Our findings could offer new perspectives in secondary research (meta-research).

Neuroimaging and Cognitive Evidence for Combined HIV-Alcohol Effects on the Central Nervous System: A Review.

Alcohol use disorder (AUD) among people living with HIV (PLWH) is a significant public health concern. Despite the advent of effective antiretroviral therapy, up to 50% of PLWH still experience worsened neurocognition, which comorbid AUD exacerbates. We report converging lines of neuroimaging and neuropsychological evidence linking comorbid HIV/AUD to dysfunction in brain regions linked to executive function, learning and memory, processing speed, and motor control, and consequently to impairment in daily life. The brain shrinkage, functional network alterations, and brain metabolite disruption seen in individuals with HIV/AUD have been attributed to several interacting pathways: viral proteins and EtOH are directly neurotoxic and exacerbate each other's neurotoxic effects; EtOH reduces antiretroviral adherence and increases viral replication; AUD and HIV both increase gut microbial translocation, promoting systemic inflammation and HIV transport into the brain by immune cells; and HIV may compound alcohol's damaging effects on the liver, further increasing inflammation. We additionally review the neurocognitive effects of aging, Hepatitis C coinfection, obesity, and cardiovascular disease, tobacco use, and nutritional deficiencies, all of which have been shown to compound cognitive changes in HIV, AUD, and in their comorbidity. Finally, we examine emerging questions in HIV/AUD research, including genetic and cognitive protective factors, the role of binge drinking in HIV/AUD-linked cognitive decline, and whether neurocognitive and brain functions normalize after drinking cessation.

Frequency analysis of HLA-B allele in leukemia patients from a North Indian population: A case-control study

BackgroundHLA-B gene is reported to have the highest number of allelic variants among the other HLA class I genes. It is suggested that the HLA-B gene has a particular ability to affect the activity of some immune responses mainly those related to lymphoproliferative neoplasia triggered by intracellular pathogens. Although, several studies have been conducted to study HLA polymorphism and distribution of HLA alleles in different populations and ethnic groups, the scarcity of comparable findings in India encouraged us to examine the possible HLA-B leukemia association in the North Indian population. ObjectiveTo determine the allelic frequencies of HLA-B and their association with leukemia in a North Indian population. Material and methodsA total of 583 patients (case) diagnosed with leukemia as well as 1188 healthy individuals (control) were studied for a period of 4 years (February 2015–March 2019). All these samples (cases and controls) were typed for HLA-B allele by polymerase chain reaction- sequence-specific oligonucleotide probe (PCR-SSOP) method based on Luminex platform. ResultsWe found an increased frequency of HLA-B*07:02 (5.75% versus 4.42%) in cases as compared to the control group. Similarly, frequency of HLA-B*15:01 (2.3% versus 1.38%), B*15:25 (0.43% versus 0.08%), B*18:01 (3.60% versus 2.81%) and B*44:03 (8.75% versus 6.01%) were found to be increased in cases as compared to the controls. These results suggest that HLA-B*15:25 (p = 0.048, OR = 4.49, 95% CI), 38:02 (p = 0.002, OR = 3.97, 95% CI), 44:03 (p = 0.003, OR = 1.48, 95% CI) have a positive association whereas HLA-B*08:01 (p ≤0.001, OR = 0.48, 95% CI) has a negative association with leukemia. ConclusionsOur results provide the first evidence of the HLA-B allele association with leukemia in the North Indian population. Further, it is suggested that HLA-B*15:25, B*38:02, and HLA-B*44:03 alleles may play a presumptive predisposing factor while the HLA-B*08: 01 allele could be a protective genetic factor against leukemia in the North Indian population.

LIFE Child Depression - a prospective longitudinal cohort study on the origin of depressive disorders between childhood and early adulthood

LIFE Child Depression - a prospective longitudinal cohort study on the origin of depressive disorders between childhood and early adulthood LIFE Child Depression is a prospective longitudinal study on the origin and course of depressive symptoms and disorders between child- and adulthood. The aim of the study is to identify patterns of developmental courses of symptoms and disorders and to investigate the interplay of psychosocial, biological and genetic risk and protective factors in the development of depressive disorders. The present paper gives an overview on results of the study. The sample was already assessed three times. A clinical sample was recruited from two local child psychiatric in- and outpatient services in Leipzig, a control sample was recruited from a children's health check program at our medical faculty (LIFE Child Health) and from the local registration office. We found some important context- and parent-associated risk factors for depressive disorders, such as negative life events, low socioeconomic status and depression in mothers (but not in fathers). Moreover, we found some characteristic biological and cognitive-emotional characteristics of children with depressive disorders, such as low stress-related cortisol, low evaluation of own performance, and more negative cognitions in dealing with stressful situations, low self-esteem and a general impairment of emotional processing of human faces. Only some of the risk factors were found to be specific to depression. Instead, most of them can be regarded as general risk factors for psychological disorders in childhood. It is also noteworthy, that some of the risk associations were gender-specific and need to be looked at from a differential point of view. Our study gives important indications for prevention for children at risk for depressive disorders as well as for therapeutic approaches.

Gene‐ and age‐informed enrichment method for preclinical Alzheimer’s disease trials: Approach and estimated cost savings

AbstractBackgroundElevated β‐amyloid (Aβ) is used to enroll clinically normal (CN) individuals in preclinical Alzheimer’s disease (AD) trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment of these individuals while reducing costs. We hypothesized that by combining a polygenic hazard score (PHS) and age‐specific risk for AD we could predict elevated Aβ in CN individuals.MethodAD incidence rates and each participant’s PHS were used to adjust the participant’s chronological age based on protective or deleterious genetic factors, thus creating an ADAge. An individual’s ADAge is defined as the chronological age at which there is equivalent AD risk in the population. Meng’s test was used in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to assess whether the ADAge was more correlated with Aβ than was chronological age. An ADAge cutpoint was chosen to optimally predict Aβ positivity among 306 CN participants from the ADNI and applied to 1000 bootstrap samples of an independent validation cohort of 80 CN participants from the UC San Diego Shiley‐Marcos Alzheimer’s Disease Research Center. The differences in means between samples enrolled by each strategy (ADAge enrichment vs no enrichment) were calculated to determine the efficiency of ADAge‐informed Aβ screening for preclinical AD trials as well as to determine the impact of ADAge enrichment on trial population demographics. The screening cost for enrolling 1000 Aβ+ CN participants in a clinical trial using each enrollment strategy was compared.ResultCompared to chronological age, ADAge was more correlated with Florbetapir SUVR in the ADNI cohort (p &lt; .001). In the validation cohort, the ADAge‐enriched sample had a higher proportion of individuals with elevated Aβ (difference[95% CI] 0.19[0.07–0.33]) than the unenriched sample. The ADAge‐enriched sample was older than the unenriched sample (difference 3.00[0.94 – 5.22]). However, the samples were similar in the proportion of APOE ε4 carriers, the dementia rating scale score, and the proportion of female participants. ADAge enrichment lowered screening costs by $5.3 million (34%) in a clinical trial scenario.ConclusionADAge enrichment provides for a more efficient and cost‐effective means to enroll CN individuals with elevated Aβ in clinical trials.

Association of TOMM40, CHAT and SORL1 Polymorphisms with the Alzheimer’s Disease in the Turkish-speaking Azeri population in Northwest of Iran

Recent genome-wide association studies have introduced several genetic variants which contribute to the late-onset Alzheimer's disease (LOAD). Polymorphisms of CHAT, TOMM40, and SORL1 genes have been reported to be associated with the LOAD phenotype. This study was endeavored to evaluate the association of the CHAT rs3810950, TOMM40 rs1160985 and SORL1 rs11218304 polymorphisms with the LOAD in the Turkish-speaking Azeri population of northwest Iran. In a case-control study, we included 174 cases: 88 cases with LOAD diagnosis and 86 healthy individuals. Peripheral blood samples were collected and the genomic DNA of all participants were extracted. Genotyping was carried out by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. We did not observe any significant association between the CHAT rs3810950 and SORL1 rs11218304 alleles with the LOAD. However, both the TOMM40 rs1160985 minor allele T and TT genotype showed significant negative associations with the LOAD. Hence, the TOMM40 rs1160985 polymorphism could be considered as a protective genetic factor against the LOAD in the Turkish-speaking Azeri population of northwest Iran.

Elucidation of the Mechanism by Which a ADAMTS5 Gene MicroRNA-Binding Site Single Nucleotide Polymorphism Affects the Risk of Osteoarthritis.

Purpose: The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) within the 3' untranslated region of the microRNA (miRNA)-binding site of the ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) gene and the risk of knee osteoarthritis (KOA) and its mechanism. Materials and Methods: Sanger sequencing was used to determine the genotypes of three ADAMTS5 gene SNPs (rs3171407, rs229071, and rs229077) from 310 patients suffering from osteoarthritis of the knee joint (KOA) and 310 healthy controls. The levels of the miRNAs, thsa-miR-103b, hsa-miR-144-3p, and hsa-miR-105-5p in plasma, and the level of ADAMTS5 mRNA in the articular cartilage of 132 patients with KOA were detected by real-time quantitative PCR. Results: The G allele at the rs3171407 locus of the ADAMTS5 gene was demonstrated to be a protective genetic factor for KOA. In addition, the risk of developing KOA was significantly increased in subjects carrying the C allele at the rs229071 locus. The risk of developing KOA in carriers of the G allele at locus rs229077 was 1.49 times greater than those with the A allele. The level of the hsa-miR-144-3p was increased, and the expression level of the ADAMTS5 protein was decreased in carriers of the T allele at the rs229071 locus. In carriers of rs229077 locus A allele the hsa-miR-105-5p level was increased and the expression level of ADAMTS5 protein was decreased. Conclusion: SNPs at the rs3171407, rs229071, and rs229077 loci of the ADAMTS5 gene are related to the risk of OA. The likely mechanism underlying these observations is that these SNPs affect the regulation of ADAMTS5 protein expression through miRNAs; however, this needs to be verified using in vivo models.

M136. PSYCHOSIS POLYRISK SCORE (PPS): IMPROVING DETECTION OF INDIVIDUALS AT-RISK AND PREDICTION OF CLINICAL OUTCOMES

BackgroundPrimary prevention in Clinical High Risk for psychosis (CHR-P) can ameliorate the course of psychotic disorders. Further advancements of knowledge have been slowed by the standstill of the field, which is mostly attributed to its epidemiological weakness. This underlies the limited identification power for at-risk individuals and the relatively modest ability of CHR-P interviews to rule-in a state of risk for psychosis. One potential avenue for improving identification of individuals at risk for psychosis is a Psychosis Polyrisk Score (PPS) integrating genetic and non-genetic risk and protective factors for psychosis. The PPS hinges on recent findings that risk enrichment in CHR-P samples is accounted for by the accumulation of non-genetic factors e.g. parental and sociodemographic risk factors, perinatal risk factors, later risk factors, and antecedents.MethodsA prototype of the PPS has been developed encompassing 26 non-genetic risk and protective factors, utilising Relative Risks (RR) from an umbrella review of risk and protective factors for psychosis onset in the general population. This was combined with prevalence data to ensure positive scores indicated increased psychosis risk and negative scores indicated decreased psychosis risk. To pilot this, patients referred for a CHR-P assessment (n=15) and healthy controls (n=66) were recruited and assessed with the PPS. Additionally, to investigate the range and distribution of these scores in the general population, 10,000,000 permutations were run utilising prevalence data to produce a simulated dataset.ResultsIn the simulated general population data, scores ranged from -15 (least risk, equivalent RR = 0.03) to 39.5 (highest risk, RR = 8912.51). 50% of individuals had an RR < 1 (PPS < 0), 26.7% of individuals had an RR > 3 (PPS > 5), and 2.7% RR > 30 (PPS > 15). Patients referred for a CHR-P assessment had higher PPS scores (median=9, IQR=12.75) than healthy controls (median=-1.75, IQR=8.875). PPS scores in the simulated general population dataset (median=0, IQR=9.5) were similarly lower than patients.DiscussionThe PPS has potential for improving identification of individuals at risk for psychosis. Its distribution in a simulated general population is reflective of expected psychosis risk, with the vast majority of people not being at-risk and very few being at high risk. In addition to supplementing current assessments for CHR-P, this could be implemented at an earlier stage to stratify individuals based on psychosis risk and inform prognoses and clinical decision-making. This promise warrants further research to ascertain its prognostic accuracy and optimal thresholds for clinical intervention.

TLR5 Activation Exacerbates Airway Inflammation in Asthma.

Innate immune activation through exposure to indoor and outdoor pollutants is emerging as an important determinant of asthma severity. For example, household levels of the bacterial product lipopolysaccharide (LPS) are associated with increased asthma severity. We hypothesized that activation of the innate immune receptor TLR5 by its bacterial ligand flagellin will exacerbate airway inflammation and asthma symptoms. We determined the effect of flagellin co-exposure with ovalbumin in a murine model of allergic asthma. We evaluated the presence of flagellin activity in house dust of asthma patients. Finally, we analyzed the association of a dominant-negative polymorphism in TLR5 (rs5744168) with asthma symptoms in patients with asthma. We showed that bacterial flagellin can be found in the house dust of patients with asthma and that this bacterial product exacerbates allergic airway inflammation in an allergen-specific mouse model of asthma. Furthermore, a dominant-negative genetic polymorphism in TLR5, the receptor for flagellin, is associated with decreased symptoms in patients with asthma. Together, our results reveal a novel genetic protective factor (TLR5 deficiency) and a novel environmental pollutant (microbial flagellin) that influence asthma severity. (Clinical trials NCT01688986 and NCT01087307).

Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities

Schizophrenia (Scz), autism spectrum disorder (ASD) and intellectual disability are common complex neurodevelopmental disorders. Kainate receptors (KARs) are ionotropic glutamate ion channels involved in synaptic plasticity which are modulated by auxiliary NETO proteins. Using UK10K exome sequencing data, we interrogated the coding regions of KAR and NETO genes in individuals with Scz, ASD or intellectual disability and population controls; performed follow-up genetic replication studies; and, conducted in silico and in vitro functional studies. We found an excess of Loss-of-Function and missense variants in individuals with Scz compared with control individuals (p = 1.8 × 10−10), and identified a significant burden of functional variants for Scz (p < 1.6 × 10−11) and ASD (p = 6.9 × 10−18). Single allele associations for 6 damaging missense variants were significantly replicated (p < 5.0 × 10−15) and confirmed GRIK3 S310A as a protective genetic factor. Functional studies demonstrated that three missense variants located within GluK2 and GluK4, GluK2 (K525E) and GluK4 (Y555N, L825W), affect agonist sensitivity and current decay rates. These findings establish that genetic variation in KAR receptor ion channels confers risk for schizophrenia, autism and intellectual disability and provide new genetic and pharmacogenetic biomarkers for neurodevelopmental disease.

Genetic Protective Factors for Dementia Isolated by Centenarian Researches

Due to the recent rapid increase in the number of elderly people in the world, health management and maintenance in elderly people have become important issues. Centenaria, who are older than 100 years, tend to stay independent in their daily life with maintenance of cognitive function until the later stage of their life compared with elderly people who die earlier. In this review, we summarize the characteristics of centenarians, the genetic risk and protective factors for longevity, and intersections between research on centenarians and dementia research.

Genetic resilience to Alzheimer's disease in APOE ε4 homozygotes: A systematic review

IntroductionIndividuals with homozygosity for the apolipoprotein E (APOE) ε4 allele are in the highest risk category for late-onset Alzheimer's disease (LOAD). However, some individuals in this category do not develop LOAD beyond the age of 75 years, despite being at elevated genetic risk. These “resilient” individuals may carry protective genetic factors. MethodsThis study aimed to systematically review any previous studies that involved resilient APOE ε4 homozygotes and to identify possible modifying or protective genetic factors. ResultsFifteen studies met our inclusion criteria and reported genetic factors contributing to reduced risk. We found that only two single nucleotide polymorphisms, CASP7 rs10553596 and SERPINA3 rs4934-A/A, had strong evidence. DiscussionWe found a paucity of studies adequately designed to discover protective genetic factors against LOAD. Many studies combined APOE ε4 homozygotes and heterozygotes together because of small sample sizes and used control populations too young to be clearly defined as controls for LOAD.

Bridging Representation Gaps in Big Data: An Alzheimer's Disease Neuroimaging Initiative (ADNI) Investigation

Abstract Objective Large-scale research consortium studies are increasingly used to help aid in early identification of age-related brain changes and neurodegenerative disease risk. Racial/ethnic minorities (REM) are severely underrepresented in publicly available datasets related to neurodegenerative disease. This is problematic given that the US older adult population will be comprised of 40% REM by 2050. As this population grows more diverse, it is crucial that Alzheimer’s disease (AD) risk factors are appropriately characterized and REM are represented in longitudinal research. The purpose of this study was to examine memory, Apolipoprotein E (APOE) status, and hippocampal volume (HV) data among REM participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Participants and Method We sampled 91 Latinx and Non-Hispanic Black (NHB) ADNI participants, which included 41 controls (CN; 39% Latinx) and 50 individuals with mild cognitive impairment (MCI; 52% Latinx). Measures included Logical Memory (LM) Delay, Rey Auditory Verbal Learning Test (RAVLT), Alzheimer’s Disease Assessment Cognitive 13-item Scale (ADAS13), APOE e4 and APOE e2 status, and HV. Groups did not differ by age, education, or memory performance. None of the Latinx sample were e2 carriers, whereas 32% of NHB were e2 carriers. Results For NHB and Latinx MCI groups, LM Delay scores positively predicted greater HV (NHB: R2 = .17, p = .04; Latinx: R2 = .16, p = .04). Better RAVLT performance predicted greater HV for the Latinx MCI group but not for the NHB MCI group (Latinx: R2 = .13, p = .06). For NHB CN, e4 status and ADAS13 were positively correlated (r = .59, p = .002) but negatively correlated for Latinx CN (r = -.58, p = .002). APOE e2 and RAVLT percent forgetting were negatively correlated for NHB MCI (r = -.49, p = .01). Conclusions There appears to be differential risk associated with heterozygous e4 status in Latinx and NHB. APOE e2 may have been protective in the context of e4 in NHB. The degree to which e2 is protective in Latinx is unknown. Results highlight the need for improved REM representation in large-scale studies to understand genetic risk and protective factors in REM.

What Causes the Onset of Psychosis in Individuals at Clinical High Risk? A Meta-analysis of Risk and Protective Factors.

Twenty percent of individuals at clinical high risk for psychosis (CHR-P) develop the disorder within 2 years. Extensive research has explored the factors that differentiate those who develop psychosis and those who do not, but the results are conflicting.The current systematic review and meta-analysis comprehensively addresses the consistency and magnitude of evidence for non-purely genetic risk and protective factors associated with the risk of developing psychosis in CHR-P individuals. Random effects meta-analyses, standardized mean difference (SMD) and odds ratio (OR) were used, in combination with an established stratification of evidence that assesses the association of each factor and the onset of psychotic disorders (from class I, convincing evidence to class IV weak evidence), while controlling for several types of biases.A total of 128 original controlled studies relating to 26 factors were retrieved. No factors showed class I-convincing evidence. Two further factors were associated with class II-highly suggestive evidence: attenuated positive psychotic symptoms (SMD = 0.348, 95% CI: 0.280, 0.415) and global functioning (SMD = −0.291, 95% CI: −0.370, −0.211). There was class III-suggestive evidence for negative psychotic symptoms (SMD = 0.393, 95% CI: 0.317, 0.469). There was either class IV-weak or no evidence for all other factors.Our findings suggest that despite the large number of putative risk factors investigated in the literature, only attenuated positive psychotic symptoms, global functioning, and negative psychotic symptoms show suggestive evidence or greater for association with transition to psychosis. The current findings may inform the refinement of clinical prediction models and precision medicine in this field.

Psychosis Polyrisk Score (PPS) for the Detection of Individuals At-Risk and the Prediction of Their Outcomes.

Primary prevention in individuals at Clinical High Risk for psychosis (CHR-P) can ameliorate the course of psychotic disorders. Further advancements of knowledge have been slowed by the standstill of the field, which is mostly attributed to its epidemiological weakness. The latter, in turn, underlies the limited identification power of at-risk individuals and the relatively modest ability of CHR-P interviews to rule-in a state of risk for psychosis. In the first part, this perspective review discusses these limitations and traces a new approach to overcome them. Theoretical concepts to support a Psychosis Polyrisk Score (PPS) integrating genetic and non-genetic risk and protective factors for psychosis are presented. The PPS hinges on recent findings indicating that risk enrichment in CHR-P samples is accounted for by the accumulation of non-genetic factors such as: parental and sociodemographic risk factors, perinatal risk factors, later risk factors, and antecedents. In the second part of this perspective review we present a prototype of a PPS encompassing core predictors beyond genetics. The PPS prototype may be piloted in the next generation of CHR-P research and combined with genetic information to refine the detection of individuals at-risk of psychosis and the prediction of their outcomes, and ultimately advance clinical research in this field.

Developing an Epidemiologic Study to Investigate Risk Factors for Colorectal Cancer Among Alaska Native People.

Alaska Native (AN) people have among the highest rates of colorectal cancer (CRC) recorded globally. Preventing CRC is an important health priority of AN tribal health leaders and communities. Lifestyle and genetic risk and protective factors for CRC among AN people remain understudied. We have been working to establish a tribally led, community-based, comprehensive investigation of lifestyle and genetic risk and protective factors for CRC among AN people. We describe the process of initiating this research study, including conversations with key tribal health system staff. We discuss themes that arose during these conversations and literature review and describe how those themes were used during the study design and protocol development phase. This description is intended to provide guidance to other researchers working to establish community-based studies of cancer risk, particularly among tribal communities.

Associations between polymorphisms of the PDLIM4 gene and susceptibility to osteoporotic fracture in an elderly population of Han Chinese.

The aim of the present study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the PDZ and LIM domain protein 4 (PDLIM4) gene and susceptibility to osteoporotic fracture in an elderly Han Chinese population. Seven SNPs of PDLIM4, including rs77584624, rs78418541, rs270611, rs3900945, rs77486529, rs71583465, and rs366512, were examined in 540 elderly Chinese patients with osteoporotic fractures (case group) and 540 healthy Chinese subjects (control group) using Sanger sequencing. A-allele carriers of rs270611 in PDLIM4 had a significantly high risk of osteoporotic fracture (adjusted odds ratio [OR] = 1.34; 95% confidence interval [CI]: 1.24–1.46; P<0.001). Similarly, individuals carrying the C-allele at PDLIM4 rs3900945 were predisposed to osteoporotic fracture (adjusted OR = 1.45; 95% CI: 1.05–1.25; P<0.001). In contrast, the T-allele at rs366512 appeared to be a protective genetic factor against osteoporotic fracture (adjusted OR = 0.84; 95% CI: 0.74–0.95; P<0.01). Consistently, the serum levels of N-terminal propeptide of type I procollagen (PINP) and C-telopeptide fragments of Collagen type I α1 chains (β-CTx) were higher in A-allele carriers of rs270611 and C-allele carriers of rs3900945, while T-allele carriers of rs366512 had lower PINP and β-CTx levels. Corresponding well with published findings, the A-allele of rs270611 and C-allele of rs3900945 were associated with reduced bone marrow density (BMD) at the fracture site, while T-allele carriers of rs366512 were shown to have normal BMD. Our study provides supportive evidence for the contribution of PDLIM4 gene polymorphisms to the susceptibility to osteoporotic fracture and suggests that rs270611 and rs3900945 are genetic risk factors, while rs366512 might be a genetic protective factor against osteoporotic fracture in elderly Han individuals.