A framework for automated gene selection in genomic applications.

PURPOSE: An efficient framework to identify disease-associated genes is needed to evaluate genomic data for both individuals with an unknown disease etiology and those undergoing genomic screening. Here, we propose a framework for gene selection used in genomic analyses, including applications limited to genes with strong or established evidence levels and applications including genes with less or emerging evidence of disease association. METHODS: We extracted genes with evidence for gene-disease association from the Human Gene Mutation Database, OMIM, and ClinVar to build a comprehensive gene list of 6,145 genes. Next, we applied stringent filters in conjunction with computationally curated evidence (DisGeNET) to create a restrictive list limited to 3,929 genes with stronger disease associations. RESULTS: When compared to manual gene curation efforts, including the Clinical Genome Resource, genes with strong or definitive disease associations are included in both gene lists at high percentages, while genes with limited evidence are largely removed. We further confirmed the utility of this approach in identifying pathogenic and likely pathogenic variants in 45 genomes. CONCLUSION: Our approach efficiently creates highly sensitive gene lists for genomic applications, while remaining dynamic and updatable, enabling time savings in genomic applications.

Disclosing genetic risk for coronary heart disease: effects on perceived personal control and genetic counseling satisfaction.

We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45-65 years) were randomized to receive estimated 10-year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 ± 2.7 vs 24.1 ± 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 ± 5.3 vs 15.9 ± 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation.

Are physicians prepared for whole genome sequencing? a qualitative analysis.

Although the integration of whole genome sequencing (WGS) into standard medical practice is rapidly becoming feasible, physicians may be unprepared to use it. Primary care physicians (PCPs) and cardiologists enrolled in a randomized clinical trial of WGS received genomics education before completing semi-structured interviews. Themes about preparedness were identified in transcripts through team-based consensus-coding. Data from 11 PCPs and 9 cardiologists suggested that physicians enrolled in the trial primarily to prepare themselves for widespread use of WGS in the future. PCPs were concerned about their general genomic knowledge, while cardiologists were concerned about how to interpret specific types of results and secondary findings. Both cohorts anticipated preparing extensively before disclosing results to patients by using educational resources with which they were already familiar, and both cohorts anticipated making referrals to genetics specialists as needed. A lack of laboratory guidance, time pressures, and a lack of standards contributed to feeling unprepared. Physicians had specialty-specific concerns about their preparedness to use WGS. Findings identify specific policy changes that could help physicians feel more prepared, and highlight how providers of all types will need to become familiar with interpreting WGS results.

FASTKD2 is associated with memory and hippocampal structure in older adults.

Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.

APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.

Deposition of amyloid-ß (Aß) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aß load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aß levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aß load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aß levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aß deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aß burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment.

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Impact of colonoscopic screening in male and female Lynch syndrome carriers with an MSH2 mutation.

The lifetime risk of developing colorectal cancer (CRC) in Lynch syndrome (LS) carriers is very high. To determine the impact of colonoscopic screening in 54 male and 98 female MSH2 mutation carriers, outcomes were compared with 94 males and 76 females who were not screened. CRC incidence and survival in the screened group were compared to that expected, derived from the non-screened group. To correct for survivor bias, controls were matched for age at entry into screening and also for gender. In males, median age to CRC was 58 years, whereas expected was 47 years (p = 0.000), and median survival was 66 years vs 62 years (p = 0.034). In screened females, median age to CRC was 79 years compared to 57 years in the non-screened group (p = 0.000), and median survival was 80 years compared with expected of 63 years (p = 0.001). Twenty percent of males and 7% of females developed an interval CRC within 2 years of previous colonoscopy. Although colonoscopic screening was associated with decreased CRC risk and better survival, CRCs continued to occur. CRC development may be further reduced by decreasing the screening interval to 1 year and improving quality of colonoscopy.

The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer's disease.

OBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study. METHODS: A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory - Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates. RESULTS: At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total. CONCLUSIONS: Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications.

Multidimensional predictors of fatigue among octogenarians and centenarians.

BACKGROUND: Fatigue is a common and frequently observed complaint among older adults. However, knowledge about the nature and correlates of fatigue in old age is very limited. OBJECTIVE: This study examined the relationship of functional indicators, psychological and situational factors and fatigue for 210 octogenarians and centenarians from the Georgia Centenarian Study. METHODS: Three indicators of functional capacity (self-rated health, instrumental activities of daily living, physical activities of daily living), two indicators of psychological well-being (positive and negative affect), two indicators of situational factors (social network and social support), and a multidimensional fatigue scale were used. Blocked multiple regression analyses were computed to examine significant factors related to fatigue. In addition, multi-group analysis in structural equation modeling was used to investigate residential differences (i.e., long-term care facilities vs. private homes) in the relationship between significant factors and fatigue. RESULTS: Blocked multiple regression analyses indicated that two indicators of functional capacity, self-rated health and instrumental activities of daily living, both positive and negative affect, and social support were significant predictors of fatigue among oldest-old adults. The multiple group analysis in structural equation modeling revealed a significant difference among oldest-old adults based on residential status. CONCLUSION: The results suggest that we should not consider fatigue as merely an unpleasant physical symptom, but rather adopt a perspective that different factors such as psychosocial aspects can influence fatigue in advanced later life.

Life events and personality predicting loneliness among centenarians: findings from the Georgia Centenarian Study.

Regarding the purpose of this study, the researchers analyzed the roles that both life events (life-time positive events and life-time negative events) and personality (Neuroticism, Extraversion, Trust, Competence, and Ideas) played in participants of the Georgia Centenarian Study. The researchers analyzed these variables to determine whether they predicted loneliness. Analyses indicated that life-time negative events significantly predicted loneliness. In essence, the higher was the number of life-time negative life events, the higher was the loneliness score. Moreover, Neuroticism, Competence, and Ideas were all significant predictors of loneliness. The higher was the level of Neuroticism and intellectual curiosity, the higher was the level of loneliness, whereas the lower was the level of Competence, the higher was the level of loneliness. In addition, both life-time positive and life-time negative life events were significant predictors of Neuroticism. The higher was the number of life-time positive events, the lower was the level of Neuroticism, and the higher was the number of life-time negative events, the greater was the level of Neuroticism. These results indicated that life-time negative events indirectly affect loneliness via Neuroticism. Last, our results indicated that the Competence facet mediated the relationship between lifetime negative life events and loneliness. Life-time negative life events significantly affected centenarians' perceived competence, and Competence in turn significantly affected the centenarians' loneliness. These results as a whole not only add to our understanding of the link between personality and loneliness, but also provide new insight into how life events predict loneliness.

Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients.

BACKGROUND: In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs. METHODS: Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival. RESULTS: In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4-7.4, P<10(-6)) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9-21.7, P<10(-17)), but was not associated with patient survival. Concordant results were obtained in Newfoundland. CONCLUSION: Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC.

Using Alzheimer's disease as a model for genetic risk disclosure: implications for personal genomics.

Susceptibility testing for common, complex adult-onset diseases is projected to become more commonplace as the rapid pace of genomic discoveries continues, and evidence regarding the potential benefits and harms of such testing is needed to inform medical practice and health policy. Apolipoprotein E (APOE) testing for risk of Alzheimer's disease (AD) provides a paradigm in which to examine the process and impact of disclosing genetic susceptibility for a prevalent, severe and incurable neurological condition. This review summarizes findings from a series of multi-site randomized clinical trials examining psychological and behavioral responses to various methods of genetic risk assessment for AD using APOE disclosure. We discuss challenges involved in disease risk estimation and communication and the extent to which participants comprehend and perceive utility in their genetic risk information. Findings on the psychological impact of test results are presented (e.g. distress), along with data on participants' health behavior and insurance purchasing responses (e.g. long-term care). Finally, we report comparisons of the safety and efficacy of intensive genetic counseling approaches to briefer models that emphasize streamlined processes and educational materials. The implications of these findings for the emerging field of personal genomics are discussed, with directions identified for future research.

The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. METHODS: Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours. RESULTS: 4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX). CONCLUSIONS: Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.

Family history and adaptation among centenarians and octogenarians.

BACKGROUND: The purpose of this study was to analyze various 'family history' variables (i.e. childhood health, financial situation while growing up, living with grandparents before age 17, and number of children) among participants of the Georgia Centenarian Study. OBJECTIVE: To determine whether family history variables predict critical outcome areas such as cognitive functioning, activities of daily living, mental health, and economic dependence. METHODS: A total of 318 older adults (236 centenarians and 82 octogenarians) were assessed with regard to their mental status, ADL (activities of daily living) functioning, depression, family history, loneliness, and perceived economic status. RESULTS: Analyses indicated that the number of children significantly predicted the ability to engage in activities of daily living and loneliness. In essence, the more children, the higher the activities of the daily living score and the lower the loneliness scores. In addition, childhood health significantly predicted loneliness. The poorer one's health in childhood, the higher the loneliness scores. CONCLUSION: The results of this study confirm the importance of distal family history variables on present-day functioning.

Predicting happiness among centenarians.

BACKGROUND: Happiness is believed to evolve from the comparison of current circumstances relative to past achievement. However, gerontological literature on happiness in extreme old age has been limited. OBJECTIVE: The purpose of this study was to determine how perceptions of health, social provisions, and economics link past satisfaction with life to current feelings of happiness among persons living to 100 years of age and beyond. METHODS: A total of 158 centenarians from the Georgia Centenarian Study were included to conduct the investigation. Items reflecting congruence and happiness from the Life Satisfaction Index were used to evaluate a model of happiness. Pathways between congruence, perceived economic security, subjective health, perceived social provisions, and happiness were analyzed using structural equation modeling. RESULTS: Congruence emerged as a key predictor of happiness. Furthermore, congruence predicted perceived economic security and subjective health, whereas perceived economic security had a strong influence on subjective health status. CONCLUSION: It appears that past satisfaction with life influences how centenarians frame subjective evaluations of health status and economic security. Furthermore, past satisfaction with life is directly associated with present happiness. This presents implications relative to understanding how perception of resources may enhance quality of life among persons who live exceptionally long lives.

Depression among centenarians and the oldest old: contributions of cognition and personality.

BACKGROUND: An estimated 20% of adults over the age of 55 experience clinical mental disorders such as depression and anxiety. For older adults, mental health concerns are often undetected, concomitant with physical challenges, and ultimately go untreated. These realities have significant implications for older adults' day-to-day functioning, particularly among the oldest old. OBJECTIVE: The present study examined the ability of cognition and personality in explaining depression within a sample of octogenarians and centenarians. METHODS: Participants were assessed during the most recent cross-sectional data collection of the Georgia Centenarian Study. The final eligible sample included 76 octogenarians (mean: 84.25 years, SD: 2.82; range: 81-90) and 158 centenarians and near centenarians (mean: 99.82 years, SD: 1.72; range: 98-109). RESULTS: Hierarchical regression analyses were conducted to examine the relation between key variables and depressive symptoms in the two age groups. Blocks entered into the analyses included: demographics (i.e. age group, residential status, sex, and ethnicity) and functioning, memory and problem-solving ability, and personality (i.e. extraversion and neuroticism). Models differed for octogenarians and centenarians. Decreased problem-solving ability was related to greater depressive symptoms among octogenarians. For centenarians, institutional residence and increased neurotic tendencies were related to greater depressive symptoms. CONCLUSION: Study findings demonstrate the need to examine a variety of factors which influence mental health in later life and to consider the unique contexts and differential experiences of octogenarians and centenarians.

Distal and proximal resource influences on economic dependency among the oldest old.

BACKGROUND: As exceptional survivors, centenarians may have characteristics that reduce their dependency on family and community support systems despite the expectation that their extreme age creates a burden on those systems. The Georgia Centenarian Study obtained information about assistance for income, medical care, and caregiving of all types for a sample of centenarians and octogenarians. Previous studies have not established which characteristics may contribute to economic dependency among the oldest old. OBJECTIVE: To identify distal and proximal resource influences on economic dependency, considering past lifestyle, proximal health, economic resources, personality, and coping behavior. METHODS: Analysis sample sizes ranged from 109 to 138 octogenarians and centenarians. Blockwise multiple regressions predicted whether they received income assistance, number of medical care events, number of caregiving types, and total caregiving hours. RESULTS: Past life style, gender, ethnicity, socioeconomic status, functional health, and coping were not related to economic dependency. With the exception of the number of types of care, centenarians were not more dependent than octogenarians. Cognitive ability had the strongest effects for medical care and caregiving services. 'Extraversion', 'ideas', 'neuroticism', and 'competence' personality factors had significant effects for caregiving types and total hours of care received. CONCLUSION: Monitoring and intervention to maintain cognitive ability are critical practices for autonomy and reduced economic dependency among the oldest old. Psychological resources are more important influences on social support than functional health and other proximal economic resources.

Social resources and longevity: findings from the Georgia centenarian study.

BACKGROUND: As the proportion of adults aged 85 and older increases, investigations of resources essential for adapting to the challenges of aging are required. OBJECTIVE: To comprehensively investigate the social resources of cognitively intact centenarians participating in the Georgia Centenarian Study and the association between these resources and residence status. METHODS: Two widely used measures of social resources were investigated among participants living in private homes, personal care facilities, and nursing homes. Logistic regression was used to determine significant predictors of nursing home residence. RESULTS: Differences in levels of social resources were found between centenarians and octogenarians, and among centenarians in different living situations. Analyses revealed differential findings between self- and proxy reports. Controlling for education, activities of daily living, and financial ability to meet needs, only one of the two social resources measures significantly reduced the odds of nursing home residence. CONCLUSION: The findings of this study add to the existing literature on one of the basic adaptive resources (social resources) for centenarians. Whether a more specific assessment of network contact is employed, or a more global assessment is used, differences in these constructs exist between centenarians and octogenarians, among centenarians in differing living conditions, and across types of informants. Researchers examining the different resources that may contribute to extraordinary longevity and positive adaptation may find it essential to differentiate between the oldest old and centenarians, and to account for differences based upon measure, reporter type, and centenarian residence status.