Biomedical subjects

Jonathan L Haines

Publications and source records attributed to Jonathan L Haines.

At least 19 recordsLinked to original sources

PubMed2026

A multiancestry polygenic risk score for Alzheimer's disease is associated with cognitive decline and neuropathological hallmarks in diverse populations.

Previously derived polygenic risk scores (PRSs) for Alzheimer's disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated with AD in European ancestry, African American, Caribbean Hispanic and Native American Hispanic groups with adjusted odds ratios between 1.14 and 1.52 per PRS standard deviation. PRS performance was validated in the replication cohorts (odds ratios: 1.21-1.65). The PRS was also associated with poorer memory, executive function and language performance, greater AD-related neuropathological burden, reduced hippocampal volume, lower cerebrospinal fluid amyloid-β42 and elevated total tau and phosphorylated tau, with stronger phosphorylated tau associations observed in women. Our findings support the value of ancestry-aware PRSs as a component of broader multimodal risk stratification frameworks.

Aged↗

PubMed2026

Can we identify people with Alzheimer's disease from examination of the eye? A bidirectional Mendelian randomization (MR) study.

BACKGROUND: Neurodegeneration in Alzheimer's disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease. METHODS: Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods. RESULTS: There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (β = 0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (β=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (β=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (β = 0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error. CONCLUSION: Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.

Humans↗

PubMed2026

Genetic modifiers of APOE-ε4-associated cognitive decline.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Humans↗

PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗

PubMed2025

A multi-ancestry polygenic risk score for Alzheimer disease is associated with cognitive decline, hippocampal atrophy and neuropathological hallmarks in diverse populations.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

Journal Article↗

PubMed2024

Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project.

INTRODUCTION: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. METHODS: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. RESULTS: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10-8). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p = 1.9 × 10-9). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 × 10-8). DISCUSSION: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD. HIGHLIGHTS: We determine the association of genetic variants with Alzheimer's disease (AD) using 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. We identified genetic variants at apolipoprotein E (APOE), BIN1, PSEN1, and LINC00320 associated with AD. We observed rare non-coding variants in the promoter of TOMM40 distinct of APOE.

Humans↗

PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗

PubMed2007

Neovascular age-related macular degeneration and its association with LOC387715 and complement factor H polymorphism.

OBJECTIVE: To compare phenotypes of 2 age-related macular degeneration (AMD) susceptibility genes: LOC387715 and complement factor H (CFH). METHODS: Phenotypes of 755 AMD cases were characterized. The number of LOC387715 (T allele at rs10490924, or A69S) and CFH (T1277C at rs1061170, or Y402H) risk alleles were determined in each case. Individuals were divided into 5 groups by genotype: group 1, LOC-/- CFH-/-; group 2, LOC+/- CFH-/- or LOC+/+ CFH-/-; group 3, LOC-/- CFH+/- or LOC-/- CFH+/+; group 4, LOC+/- CFH+/-, LOC+/+ CFH+/-, or LOC+/- CFH+/+; and group 5, LOC+/+ CFH+/+. RESULTS: Signs of neovascular AMD including grade (P = .002), pigment epithelial detachment (P = .001), and subretinal hemorrhage (P<.001) demonstrated significant association with groups 2, 4, and 5 vs groups 1 and 3. Group 5 had a significantly younger mean age (72.3 years) compared with other groups (P = .002). CONCLUSIONS: The AMD cases possessing the LOC387715 (rs10490924) variant may have a higher risk of neovascular AMD. Individuals with AMD who are homozygous for both variants might be at greater risk for earlier onset of neovascular AMD.

Aged↗

PubMed2006

Association analysis of genetic polymorphisms in the CDC2 gene with late-onset Alzheimer disease.

BACKGROUND: Alzheimer disease (AD) is a complex neurodegenerative disorder resulting from multiple genetic and non-genetic factors. Linkage studies indicated that chromosome 10 has at least one locus for this disease. The cell division cycle 2 (CDC2) gene, which is close to one of the linkage regions, has previously been associated with the risk of AD with an odds ratio of 1.78. Biologically, CDC2, which is involved in paired helical filament-tau formation, is thought as a candidate gene in AD. METHODS: In this study, six single nucleotide polymorphisms spanning the entire gene were selected and examined for association for late-onset AD (LOAD) in two large independent datasets. A family-based dataset including 1,337 Caucasian discordant sib pairs and an independent dataset of 745 Caucasian cases and 998 controls for LOAD were used. Family-based association tests and logistic regression conditional on the apolipoprotein E genotype and sex were applied to association study in family-based and case-control datasets, respectively. RESULTS: Neither dataset demonstrated any association with LOAD in our samples with all p values >0.16. CONCLUSION: Our results suggest that if any contribution of common genetic variants in CDC2 to the risk of developing AD exists, it is likely to be very small.

Aged↗

PubMed2006

A comparative analysis of the information content in long and short SAGE libraries.

BACKGROUND: Serial Analysis of Gene Expression (SAGE) is a powerful tool to determine gene expression profiles. Two types of SAGE libraries, ShortSAGE and LongSAGE, are classified based on the length of the SAGE tag (10 vs. 17 basepairs). LongSAGE libraries are thought to be more useful than ShortSAGE libraries, but their information content has not been widely compared. To dissect the differences between these two types of libraries, we utilized four libraries (two LongSAGE and two ShortSAGE libraries) generated from the hippocampus of Alzheimer and control samples. In addition, we generated two additional short SAGE libraries, the truncated long SAGE libraries (tSAGE), from LongSAGE libraries by deleting seven 5' basepairs from each LongSAGE tag. RESULTS: One problem that occurred in the SAGE study is that individual tags may have matched to multiple different genes - due to the short length of a tag. We found that the LongSAGE tag maps up to 15 UniGene clusters, while the ShortSAGE and tSAGE tags map up to 279 UniGene clusters. Both long and short SAGE libraries exhibit a large number of orphan tags (no gene information in UniGene), implying the limitation of the UniGene database. Among 100 orphan LongSAGE tags, the complete sequences (17 basepairs) of nine orphan tags match to 17 genomic sequences; four of the orphan tags match to a single genomic sequence. Our data show the potential to resolve 4-9% of orphan LongSAGE tags. Finally, among 400 tSAGE tags showing significant differential expression between AD and control, 79 tags (19.8%) were derived from multiple non-significant LongSAGE tags, implying the false positive results. CONCLUSION: Our data show that LongSAGE tags have high specificity in gene mapping compared to ShortSAGE tags. LongSAGE tags show an advantage over ShortSAGE in identifying novel genes by BLAST analysis. Most importantly, the chances of obtaining false positive results are higher for ShortSAGE than LongSAGE libraries due to their specificity in gene mapping. Therefore, it is recommended that the number of corresponding UniGene clusters (gene or ESTs) of a tag for prioritizing the significant results be considered.

Algorithms↗

PubMed2006

Complex gene-gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes.

The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene-gene interactions using complementary case-control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene-gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between approximately 61% and 85% accuracy. These results suggest that significant epistasis, or gene-gene interactions, may exist even in the absence of statistically significant individual main effects.

Case-Control Studies↗

PubMed2006

Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity.

This nested case-control study examined relationships between MDR1, CYP2B6, and CYP3A4 variants and hepatotoxicity during antiretroviral therapy with either efavirenz- or nevirapine-containing regimens. Decreased risk of hepatotoxicity was associated with MDR1 3435C-->T (odds ratio, 0.254; P=.021). An interaction between MDR1 and hepatitis B surface antigen status predicted risk with 82% accuracy (P<.001).

Adult↗

PubMed2006

Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.

Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Adult↗

PubMed2006

GATA2 is associated with familial early-onset coronary artery disease.

The transcription factor GATA2 plays an essential role in the establishment and maintenance of adult hematopoiesis. It is expressed in hematopoietic stem cells, as well as the cells that make up the aortic vasculature, namely aortic endothelial cells and smooth muscle cells. We have shown that GATA2 expression is predictive of location within the thoracic aorta; location is suggested to be a surrogate for disease susceptibility. The GATA2 gene maps beneath the Chromosome 3q linkage peak from our family-based sample set (GENECARD) study of early-onset coronary artery disease. Given these observations, we investigated the relationship of several known and novel polymorphisms within GATA2 to coronary artery disease. We identified five single nucleotide polymorphisms that were significantly associated with early-onset coronary artery disease in GENECARD. These results were validated by identifying significant association of two of these single nucleotide polymorphisms in an independent case-control sample set that was phenotypically similar to the GENECARD families. These observations identify GATA2 as a novel susceptibility gene for coronary artery disease and suggest that the study of this transcription factor and its downstream targets may uncover a regulatory network important for coronary artery disease inheritance.

Adult↗

PubMed2006

Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.

OBJECTIVE: Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN. DESIGN: Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens. METHODS: Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression. RESULTS: : Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddI plus d4T. Among ddI/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddI/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (CI) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042]. CONCLUSIONS: Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.

Adolescent↗

PubMed2006

Complement factor H increases risk for atrophic age-related macular degeneration.

OBJECTIVE: To determine if the complement factor H gene (CFH) determines risk for development of geographic atrophy (GA). DESIGN: Retrospective case-control study. PARTICIPANTS AND CONTROLS: The independent case-control data set contained 647 age-related macular degeneration (AMD) cases (grades 3, 4, or 5) and 163 controls (grades 1 or 2). METHODS: To determine if CFH had any effect on determining risk for development of GA in an independent case-control data set of 647 AMD cases and 163 controls, the rs1061170 single-nucleotide polymorphism was tested for association, separating grades and analyzing them independently against the controls. Odds ratios were calculated using standard logistic regression models. MAIN OUTCOME MEASURES: The outcome variable was AMD affection status, and genotypes were coded according to a log-additive model. RESULTS: There were 407 grade 5, 107 grade 4, 133 grade 3, 35 grade 2, and 128 grade 1 individuals. There was significant association with AMD when comparing grades 3, 4, and 5 versus the controls. The highest odds ratio was obtained when analyzing the grade-4 cases versus the grade-1 controls (OR = 3.217, P<0.0001). CONCLUSIONS: Our results indicate that CFH increases the risk of developing GA (grade 4) as well as neovascular (grade 5) and milder (grade 3) disease. Although neovascular disease is responsible for the majority of severe vision loss with AMD, GA is also a significant cause of vision loss, and without effective treatment. Therefore, an attempt to clarify its pathogenesis is of the utmost importance.

Aged↗

PubMed2006

Investigation of autism and GABA receptor subunit genes in multiple ethnic groups.

Autism is a neurodevelopmental disorder of complex genetics, characterized by impairment in social interaction and communication, as well as repetitive behavior. Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in autistic patients, indicate that the GABAergic system, which is responsible for synaptic inhibition in the adult brain, may be involved in autism. Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients. Studies of genetic variation in African-American autism families are rare. Analysis of 557 Caucasian and an independent population of 54 African-American families with 35 SNPs within GABRB1 and GABRA4 strengthened the evidence for involvement of GABRA4 in autism risk in Caucasians (rs17599165, p=0.0015; rs1912960, p=0.0073; and rs17599416, p=0.0040) and gave evidence of significant association in African-Americans (rs2280073, p=0.0287 and rs16859788, p=0.0253). The GABRA4 and GABRB1 interaction was also confirmed in the Caucasian dataset (most significant pair, rs1912960 and rs2351299; p=0.004). Analysis of the subset of families with a positive history of seizure activity in at least one autism patient revealed no association to GABRA4; however, three SNPs within GABRB1 showed significant allelic association; rs2351299 (p=0.0163), rs4482737 (p=0.0339), and rs3832300 (p=0.0253). These results confirmed our earlier findings, indicating GABRA4 and GABRB1 as genes contributing to autism susceptibility, extending the effect to multiple ethnic groups and suggesting seizures as a stratifying phenotype.

Autistic Disorder↗

PubMed2006

Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis.

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate gene on chromosome 10 [LOD score increased from 0.1 in the autopsy-confirmed subset to 4.19 in the unlinked subset (optimal subset); p<0.0001 for the increase in LOD score], indicating a one-LOD support interval spanning 6 Mb. To further investigate this finding and to identify potential candidate LOAD risk genes for follow-up analysis, we analyzed 99 single nucleotide polymorphisms in this region, for the overall sample, the autopsy-confirmed subset, and the optimal subset, respectively, for comparison. We saw no significant association (p<0.01) in the overall sample. In the autopsy-confirmed subset, the best finding was obtained in the activation transcription factor 7 (ATF7) gene (single-locus association, p=0.002; haplotype association global, p=0.007). In the optimal subset, the best finding was obtained in the hypothetical protein FLJ20436 (FLJ20436) gene (single-locus association, p=0.0026). These results suggest that subset and covariate analyses may be one approach to help identify novel susceptibility genes on chromosome 12q for LOAD.

Alzheimer Disease↗