Background Autism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a ∼500–700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown. Methodology/Principal Findings To identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings. Conclusions/Significance We have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.

Background: One genetic mechanism known to be associated with autism spectrum disorders (ASD) is chromosomal abnormalities. The identification of copy number variants (CNV), i.e., microdeletions and microduplications that are undetectable at the level of traditional cytogenetic analysis, allows the potential association of submicroscopic chromosomal imbalances and human disease.Methods: We performed array comparative genomic hybridization (aCGH) utilizing a 19K whole genome tiling path bacterial artificial chromosome (BAC) microarray on 397 unrelated subjects with autism spectrum disorder. Common CNV were excluded using a control group comprised of 372 individuals from the National Institute of Mental Health (NIMH) Genetics Initiative Control samples. Confirmation studies were performed on all remaining CNV using fluorescence in situ hybridization (FISH), microsatellite analysis, and/or quantitative polymerase chain reaction (PCR) analysis.Results: A total of 51 CNV were confirmed in 46 ASD subjects. Three maternal interstitial duplications of 15q11-q13 known to be associated with AS D were identified. The other 48 CNV ranged in size from 189 kilobase (kb) to 5.5 megabase (Mb) and contained from 0 to similar to 40 National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) genes. Seven CNV were de novo and 44 were inherited.Conclusions: Fifty-one autism-specific CNV were identified in 46 of 397 ASD patients using a 19K BAC microarray for an overall rate of 11.6% . These microdeletions and microduplications cause gene dosage imbalance in 272 genes, many of which could be considered as candidate genes for autism.

Autism is a childhood neurodevelopmental disorder with a strong genetic component, yet the identification of autism susceptibility loci remains elusive. We investigated 180 autism probands and 372 control subjects by array comparative genomic hybridization (aCGH) using a 19K whole-genome tiling path bacterial artificial chromosome microarray to identify submicroscopic chromosomal rearrangements specific to autism. We discovered a recurrent 16p11.2 microdeletion in two probands with autism and none in controls. The deletion spans approximately 500-kb and is flanked by approximately 147-kb segmental duplications (SDs) that are >99% identical, a common characteristic of genomic disorders. We assessed the frequency of this new autism genomic disorder by screening an additional 532 probands and 465 controls by quantitative PCR and identified two more patients but no controls with the microdeletion, indicating a combined frequency of 0.6% (4/712 autism versus 0/837 controls; Fisher exact test P = 0.044). We confirmed all 16p11.2 deletions using fluorescence in situ hybridization, microsatellite analyses and aCGH, and mapped the approximate deletion breakpoints to the edges of the flanking SDs using a custom-designed high-density oligonucleotide microarray. Bioinformatic analysis localized 12 of the 25 genes within the microdeletion to nodes in one interaction network. We performed phenotype analyses and found no striking features that distinguish patients with the 16p11.2 microdeletion as a distinct autism subtype. Our work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date.

Background Previous studies have suggested a positive association between phenotypes of fucosyltransferase 3 (FUT3) gene (also known as Lewis. gene) and coronary heart disease.Methods We used data on 1735 unrelated subjects in the Framingham Offspring Study to assess whether 3 functional single-nucleotide polymorphisms (SNPs) of the FUT3 gene (T59G, T1067A, and T202C) were associated with prevalent atherothrombotic disease.Results Contrary to T1067A and T202C SNPs, there was evidence for an association between T59G.SNP and atherothrombotic disease prevalence. In a multivariable model controlling for age, sex, alcohol intake, pack-years of smoking, ratio of total to high-density lipoprotein cholesterol, and diabetes mellitus, ORs (95% Cl) for prevalent atherothrombotic disease were 1.0 (reference), 0.80 (0.46-1.41), and 6.70 (1.95-23.01) for TT, TG, and GG genotypes of the T59G SNP, respectively. Minor alleles of T202C and T1067A SNPs showed a modest and nonsignificant association with atherothrombotic disease. Overall, FUT3 polymorphism that influences the enzyme activity (GG genotype for T59G or :>= 1 minor allele of T202C or T1067A) was associated with increased atherothrombotic disease prevalence (OR 1.57, 1.05-2.34), and this association was stronger among abstainers (2-fold increased odds) than among current drinkers ( P for interaction 11).Conclusions Our data suggest that functional mutations of the FUT3 gene may be associated with an increased atherothrombotic disease prevalence, especially among abstainers. Additional studies are warranted to confirm these findings.

RATIONALE Previously reported linkage to FEV(1) (LOD score = 5.0) on 6q27 in the Framingham Heart Study (FHS) led us to explore a candidate gene, SMOC2, at 168.6 Mb. OBJECTIVES We tested association between SMOC2 polymorphisms and FEV(1) and FVC in unrelated FHS participants. METHODS Twenty single-nucleotide polymorphisms (SNPs) around SMOC2 were genotyped in 1,734 subjects. MEASUREMENTS AND MAIN RESULTS SNP data were analyzed using multiple linear regression models incorporating sex, age, body mass index, height, and smoking history as covariates, and analyses were repeated within strata of ever- and never-smokers. The minor allele of SNP rs1402 was associated with higher mean FEV(1) (p = 0.003) and FVC (p = 0.02) measures. In never-smoking subjects, association with higher measures was observed with the minor allele of rs747995 (FEV(1), p = 0.0006; FVC, p = 0.0008). These two SNPs lie in different haplotype blocks and reside in intron 4 of SMOC2. Haplotype analysis revealed a common G-T haplotype (rs747995-rs1402) with 77% frequency in never-smoking FHS subjects. The G-T haplotype was associated with reduction of 126 ml for FEV(1) (p = 0.0002) and 157 ml for FVC (p = 0.0002). The G-T haplotype was similarly associated in a set of never-smoking subjects from the Family Heart Study (FEV(1), p = 0.03; FVC, p = 0.03). CONCLUSIONS The replication of the association in two populations supports the possibility that SMOC2 might play an important role in the determination of FEV(1) and FVC.

The PARK3 locus on chromosome 2p13 has shown linkage to both the development and age of onset of Parkinson's disease (PD). One candidate gene at this locus is sepiapterin reductase (SPR). Sepiapterin reductase catalyzes the final step in the biosynthetic pathway of tetrahydrobiopterin (BH4), an essential cofactor for aromatic amino acid hydrolases including tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. The expression of SPR was assayed using semiquantitative real-time RT-PCR in human post-mortem cerebellar tissue from neuropathologically confirmed PD cases and neurologically normal controls. The expression of other enzymes involved in BH4 biosynthesis, including aldose reductase (AKR1B1), carbonyl reductase (CBR1 and CBR3), GTP-cyclohydrolase I (GCH1), and 6-pyruvoyltetrahydrobiopterin (PTS), was also examined. Single-nucleotide polymorphisms around the SPR gene that have been previously reported to show association to PD affection and onset age were genotyped in these samples. Expression of SPR showed a significant 4-fold increase in PD cases relative to controls, while the expression of AKR1B1 and PTS was significantly decreased in PD cases. No difference in expression was detected for CBR1, CBR3, and GCH1. Genetic variants did not show a significant effect on SPR expression, however, this is likely due to the low frequency of rare genotypes in the sample. While the association of SPR to PD is not strong enough to support that this is the PARK3 gene, this study further implicates a role for SPR in idiopathic PD.

Objective: The - 174 interleukin (IL)-6 gene polymorphism has been proposed as a risk factor for type 2 diabetes, but data are conflicting. Because white fat is a major source of IL-6 in resting individuals, we tested the hypothesis that BMI modifies the association among the IL-6 genotype, insulin resistance (IR) (measured using the homeostasis model), and risk of diabetes.Research Methods and Procedures: Outcomes were assessed in a community-based cohort study of 1525 adults (mean age, 55.6 years; 753 men), who participated in the Framingham Offspring Study during the 1991 to 1995 examinations.Results: We found a significant interaction between IL-6 genotype and BMI on levels of IR in men (p < 0.0001), with obese homozygotes for the minor C allele being most resistant. The IL-6-BMI interaction was not significant (p = 0.46) in women. Among men with the CC genotype, increasing BMI was associated with increased prevalence of diabetes [odds ratio (OR) per unit increase in BMI, 1.30; 95% confidence interval (CI), 1.11 to 1.50] but not among those with the GG (OR, 1.10; 95% Cl, 0.98 to 1.22) or GC genotype (OR, 1.05; 95% Cl, 0.97 to 1.14).Discussion: The - 174 IL-6 promoter polymorphism modifies the association of obesity with IR and diabetes risk in men. Weight loss regimens targeted at reducing the risk of diabetes may be of particular benefit for men with a - 174 IL-6 CC genotype.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA , NR4A2 , and DJ ‐ 1 genes in 292 cases of familial Parkinson's disease from the Gene PD study. None of the variants were found in the Gene PD families. Our results suggest that other variants or genes account for the familial risk of PD within the Gene PD study. © 2005 Movement Disorder Society

We evaluated the –174 IL-6 gene polymorphism as a risk factor for type 2 diabetes mellitus in a family-based analysis.

Although moderate alcohol consumption is associated with a lower risk of cardiovascular disease (CVD), little is known of the effects of alcohol dehydrogenase 1C (ADH1C) polymorphism on the association between alcohol and CVD. We used data on 1,805 unrelated subjects in the Framingham Offspring Study to assess whether rs1693482 and rs698, 2 single nucleotide polymorphisms of the ADH1C gene, modify the relation between alcohol consumption and prevalent CVD. The 2 single nucleotide polymorphisms were in linkage disequilibrium (D' = 0.99, R(2) = 0.96). There was evidence for a U-shaped association between alcohol consumption and CVD in this population. Multivariable adjusted odds ratios for prevalent CVD were 0.63 (95% confidence interval 0.41 to 0.97) and 0.80 (95% confidence interval 0.46 to 1.41) for CT and TT genotypes of rs1693482 relative to CC genotype (model p <0.0001). Corresponding values for AG and GG genotypes of rs698 were 0.68 (95% confidence interval 0.45 to 1.04) and 0.84 (95% confidence interval 0.49 to 1.46), respectively, compared with the AA genotype (model p <0.0001). There were nonstatistically significant associations between rs693482 C-->T and rs698 A-->G mutations and prevalent CVD among current drinkers (lower CVD prevalence with minor allele) but not among nondrinkers in whom the minor allele was associated with a trend toward higher CVD prevalence (p values for interaction are 0.16 for rs1693482 and 0.52 for rs698). Alcohol consumption was associated with high-density lipoprotein cholesterol across all genotypes of the 2 single nucleotide polymorphisms in a dose-response fashion without evidence for interaction. In conclusion, these data suggest borderline interactions between genes and environment of ADH1C variation and alcohol intake on prevalent CVD. The interaction does not appear to be mediated through effects on high-density lipoprotein cholesterol.

Brain-derived neurotrophic factor ( BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Lifestyle and dietary factors may influence the association of IL-6 polymorphisms with bone mass. In 1574 unrelated men and women from the Framingham Offspring Cohort, we observed significant hip BMD differences between IL-6 -174 genotypes only in older women, those without estrogens, and those with a poor calcium intake. Hence, association of IL-6 polymorphisms with BMD may be limited to discrete population subgroups.Introduction: Interleukin (IL)-6 plays a central role in the pathogenesis of osteoporosis. Two functional variants in the IL-6 promoter have previously been associated with IL-6 expression, bone resorption levels, and BMD in late postmenopausal women, but results were conflicting in different populations. We hypothesized that the association between IL-6 promoter alleles and BMD may be affected by interactions with lifestyle and dietary factors known to influence bone turnover.Materials and Methods: Among the Offspring Cohort of the Framingham Heart Study, 1574 unrelated men and women were genotyped for IL-6 -572 and -174 alleles. Interaction analyses with years since menopause, estrogen status, physical activity, smoking, dietary calcium, vitamin D, and alcohol intake were based on BMD measurements at the hip.Results and Conclusions: In models that considered only the main effects of IL-6 polymorphisms, no significant association with BMD was observed in either gender. In contrast, p values (0.003-0.096 by ANOVA) suggestive of an interaction between IL-6 -174 genotypes and years since menopause, estrogen status, dietary calcium, and vitamin D intake were observed in women (n = 819). In turn, BMD was significantly lower with genotype - 174 GG compared with CC, and intermediate with GC, in women who were more than 15 years past menopause and in those without estrogens or with calcium intake <940 mg/day. In estrogen-deficient women with poor calcium intake, BMD differences between genotypes CC and GG were 10.2% at femoral neck (p = 0.012), 12.0% at trochanter (p = 0.012), and 16.8% at Ward's area (p = 0.0014). In contrast, no such interactions were observed in men (n = 755). In conclusion, IL-6 genetic variation was prominently associated with hip BMD in late postmenopausal women, those without estrogen replacement therapy, and those with inadequate calcium intake. In contrast, IL-6 polymorphisms are unlikely to be significant determinants of bone mass in other women or men.

OBJECTIVE:To identify a haplotype influencing onset age for Parkinson's disease (PD) in the PARK3 region on chromosome 2p13.METHODS:Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families.RESULTS:TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset (p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) (SPR) gene, rs1876487 (p = 0.02) and rs1150500 (p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP-rs2421095, rs1876487, rs1561244-revealed an association with onset age (p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD (p = 0.005).CONCLUSIONS:A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Linkage studies have mapped a susceptibility gene for type 2 diabetes to the long arm of chromosome 10, where we have previously identified a quantitative trait locus that affects fasting blood glucose within the Framingham Heart Study cohort. One candidate gene in this region is the insulin-degrading enzyme (IDE), which, in the GK rat model, has been associated with nonobese type 2 diabetes. Single nucleotide polymorphisms (SNPs) were used to map a haplotype block in the 3' end of IDE, which revealed association with HbA(1c), fasting plasma glucose (FPG), and mean fasting plasma glucose (mFPG) measured over 20 years. The strongest associations were found in a sample of unrelated men. The lowest trait values were associated with a haplotype (TT, f approximately 0.32) containing the minor allele of rs2209772 and the major allele of the rs1887922 SNP (FPG P < 0.001, mFPG P < 0.003, HbA(1c) P < 0.025). Another haplotype (CC, f approximately 0.16) was associated with elevated HbA(1c) (P < 0.002) and type 2 diabetes (P < 0.001, odds ratio 1.96, 95% CI 1.28-3.00). The evidence presented supports the possibility that IDE is a susceptibility gene for diabetes in populations of European descent.