Sib Pair Study Research Articles

SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men.

Genetic variation in sex hormone-binding globulin (SHBG) structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration. To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men. Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean: 34.5) years. Genotyping using microarray (Illumina®) for SNPs suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis. Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; p < 0.05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all p < 0.05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all p < 0.05). No clear effects on measured free T were found, except for a trend towards higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; p < 0.05) in the larger global study population. In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.

Multilocus pathogenic variants contribute to intrafamilial clinical heterogeneity: a retrospective study of sibling pairs with neurodevelopmental disorders

BackgroundMultilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context.MethodsWe conducted a systematic reanalysis of exome sequencing data and runs of homozygosity (ROH) regions of 47 sibling pairs previously diagnosed with various neurodevelopmental disorders (NDD).ResultsWe found siblings with MPVs driven by long ROH regions in 8.5% of families (4/47). The patients with MPVs exhibited significantly higher FROH values (p-value = 1.4e-2) and larger total ROH length (p-value = 1.8e-2). Long ROH regions mainly contribute to this pattern; the siblings with MPVs have a larger total size of long ROH regions than their siblings in all families (p-value = 6.9e-3). Whereas the short ROH regions in the siblings with MPVs are lower in total size compared to their sibling pairs with single locus pathogenic variants (p-value = 0.029), and there are no statistically significant differences in medium ROH regions between sibling pairs (p-value = 0.52).ConclusionThis study sheds light on the significance of considering MPVs in families with affected sibling pairs and the role of ROH as an adjuvant tool in explaining clinical variability within families. Identifying individuals carrying MPVs may have implications for disease management, identification of possible disease risks to different family members, genetic counseling and exploring personalized treatment approaches.

A SNP in the 5’ flanking region of the SAA1 gene is associated with serum levels of serum amyloid A and cardiovascular risk factors

BackgroundElevated serum levels of serum amyloid A (SAA) are associated with increased risk of cardiovascular disease. In this study, we examine associations between allelic variation in the rs11024595 single nucleotide polymorphism (SNP) in the 5’ flanking region of the SAA1 gene and adipose tissue gene expression, serum levels of SAA and cardiovascular risk factors.MethodsDNA samples from 729 participants in the SibPair study, comprising weight discordant siblings and their biological parents, and 3542 participants (1783 patients treated with bariatric surgery and 1759 controls) from the Swedish Obese Subjects (SOS) study were used. The rs11024595 SNP was genotyped in both cohorts using Pyrosequencing or the Sequenom MassARRAY platform, respectively. Blood chemistry and anthropometry were assessed at study start. Adipose tissue SAA1 gene expression and serum levels of SAA in the SibPair study were analyzed with DNA microarray or immunoassay, respectively.ResultsIn the SibPair study, the rs11024595 SNP was associated with serum levels of SAA (P = 0.0050) where T allele carriers displayed lower levels of SAA (P = 0.0025) but no association between genotype and adipose tissue SAA1 gene expression was found. In the SOS study, the rs11024595 SNP was associated with serum levels of HDL cholesterol (P = 0.0045), triglycerides (P = 0.025) and apolipoprotein E (P = 0.026). Moreover, T allele carriers had lower levels of HDL cholesterol (P = 0.0148), but higher levels of triglycerides (P = 0.0418) and apolipoprotein E (P = 0.028) compared to C allele homozygotes. The rs11024595 SNP was also associated with plasma glucose (P = 0.044).ConclusionsThe rs11024595 SNP in the 5’ flanking region of the SAA1 gene is associated with both serum levels of SAA and other cardiovascular risk factors. Future studies are required to elucidate whether the rs11024595 SNP can affect the risk of cardiovascular events.Trial registrationClinicalTrials.gov Identifier: NCT01479452 Registered 24 November 2011 - retrospectively registered.

SIBLING CONCORDANCE IN SYMPTOM ONSET AND ATROPHY GROWTH RATES IN STARGARDT DISEASE USING ULTRA-WIDEFIELD FUNDUS AUTOFLUORESCENCE.

To investigate concordance in symptom onset, area of dark autofluorescence (DAF), and growth rate (GR) between Stargardt disease siblings at an age-matched time point. In this retrospective longitudinal study of sibling pairs with identical biallelic ABCA4 variants, age at symptom onset, best-corrected visual acuity, atrophy area, and effective radius of DAF on ultra-widefield fundus autofluorescence were recorded. Absolute intersibling differences for both eyes were compared with absolute interocular differences using the Mann-Whitney test. Overall 39 patients from 19 families were recruited. In 16 families, age-matched best-corrected visual acuity and DAF were compared between siblings. In 8 families, DAF GR was compared. The median (range) absolute difference in age at symptom onset between siblings was 3 (0-35) years. Absolute intersibling differences in age-matched best-corrected visual acuity were greater than interocular differences ( P = 0.01). Similarly, absolute intersibling differences in DAF area and radius were greater than interocular differences ( P = 0.04 for area and P = 0.001 for radius). Differences between absolute interocular and intersibling GR were not statistically significant ( P = 0.44 for area GR and P = 0.61 for radius GR). There was significant discordance in age-matched best-corrected visual acuity and DAF beyond the expected limits of interocular asymmetry. Lack of significant intersibling differences in GR warrants further investigation.

Gene expression profiling in peripheral blood lymphocytes for major depression: preliminary cues from Chinese discordant sib-pair study

The etiology of major depressive disorder (MDD) involves many factors such as heredity and environment. There are very few MDD-related studies in Chinese population using twin or sib-pairs for depression-control samples. Here we used the microarray approach and compared gene expression profiling of peripheral blood lymphocytes from 6 sib-pairs discordant on lifetime history of MDD. Within sib-pair differentially expressed genes are obvious fewer in the 1st, 2nd, and 5th compared with those in the 3rd, 4th, and 6th sib-pairs. Gene expression pattern of these DEGs distinguished MDD individuals from the normal one in 3rd, 4th, and 6th sib-pair but not in the 1st, 2nd, and 5th pair, suggesting heterogeneity of different sib-pairs and somewhat commonalities among the 3rd, 4th, and 6th sib-pairs. Comprehensive protein interaction network analysis revealed two key genes PTH and FGF2 in a dominant network where the majority of the genes were significantly down-regulated. PTH was significantly down-regulated in all the sib-pairs while FGF2 was in the 3rd, 4th, and 6th sib-pairs. KEGG enrichment analysis of all the DEGs in networks showed that PTH and related genes were significantly enriched in the pathway of parathyroid hormone secretion, synthesis, and action while FGF2 and related genes were significantly enriched in the pathways of cancer and specifically breast cancer. Generally reduced expression of these genes in peripheral blood lymphocytes of MDD individuals implied their functional repression associated with MDD. Pending validation in more samples, the findings in this study provided valuable cues for understanding the potential mechanism of MDD, as well as potential markers for the diagnosis and treatment of depression in the Chinese population.

Early Decline of Androgen Levels in Healthy Adult Men: An Effect of Aging Per Se? A Prospective Cohort Study.

Androgen levels have been shown to decline in aging men. However, there is no consensus on the effect of aging, (changes in) body mass index (BMI), lifestyle factors, and intercurrent disease. Investigating longitudinal changes in serum androgen levels in healthy men in relation to body composition, lifestyle factors, and intercurrent disease. Longitudinal, population-based sibling pair study at a university research center. 999 healthy men aged 24 to 46 years of whom 691 were reevaluated after a mean period of 12 years. Serum SHBG, LH, and FSH levels measured using immuno-assays. Testosterone (T), estradiol (E2), dihydro-testosterone (DHT), and androstenedione (Adione) measured using liquid chromatography-tandem mass spectometry, free T calculated (cFT). Baseline age was 34 ± 6 years. Mean BMI increased by 1.19 kg/m2, T levels decreased by 14.2% (20.8 nmol/L vs. 17.8 nmol/L), cFT by 19.1% (392 pmol/L vs. 317 pmol/L), DHT by 15.6% (1.5 nmol/L vs.1.3 nmol/L), and Adione by 10.7% (3.7 nmol/L vs. 3.3 nmol/L; all P < 0.001). E2 did not change over time. SHBG increased by 3.0% (39.8 nmol/L vs. 41.0 nmol/L), LH by 5.8% (4.6 U/L vs. 4.9 U/L) and FSH by 14.7% (4.3 U/L vs. 5.1 U/L) (all P < 0.001). For T, cFT, DHT, Adione, and SHBG, these longitudinal changes persisted after adjustment for confounders (all P < 0.001). Serum androgen levels start declining early during adult life and independently from changes in BMI and other lifestyle factors, suggesting that aging per se leads to an altered sex steroid status. Given the concurrent rise in gonadotropin levels, the decline in androgen status most likely arises from primary decrease in testicular function.

Mortality risks associated with sibling heart failure

BackgroundThe mortality in individuals with a family history of heart failure (HF) has not been determined. This nationwide sib-pair study aimed to determine mortality in individuals with a sibling affected with HF. MethodsSib-pairs were linked using the Swedish Multi-Generation Register, the Hospital Discharge Register and the Cause of Death Register for the period 1987–2012. Families with cardiomyopathy or congenital heart disease were excluded.Mortality hazard ratios (HRs) were calculated for siblings of individuals who had been diagnosed with HF compared with siblings of individuals unaffected by HF as the reference group. Similar analyses were made for spouses. HRs were determined for overall mortality, cardiovascular mortality, and death of unknown cause. ResultsAmong siblings, the adjusted HR for overall mortality was 1.21 (95% CI 1.18–1.25). This risk remained (HR = 1.19, 95% CI 1.15–1.23) also among subjects without HF themselves. The adjusted HRs for cardiovascular mortality and death of unknown cause were 1.39 (95% CI 1.32–1.45) and 1.58 (95% CI 1.29–1.95), respectively. The mortality risk associations with spousal HF were all minimal, with an overall mortality HR of 1.02 (1.01–1.02). Early sibling age of onset of HF < 50 years was associated with higher HRs for overall mortality, cardiovascular mortality, and death of unknown cause, 1.33 (1.27–1.41), 1.54 (1.40–1.68) and 1.84 (1.27–2.67), respectively. ConclusionsSibling HF, especially early-onset HF, is associated with increased mortality. The low risk in spouses suggests genetic factors might be of importance. Screening for HF, and cardiovascular disease in general, in these individuals may be warranted.

Cognitive sensitivity and child receptive vocabulary: A between- and within-family study of mothers and sibling pairs.

This study examined the association between observed cognitive sensitivity (CS) during family interactions and children's receptive vocabulary for older and younger siblings. Maternal and sibling CS was considered and associations were explored at the family-wide (between-family) and child-specific (within-family) levels of analysis. The interactions of mothers and 2 children per family were observed when younger siblings were 3.15 years (SD = 0.27) and older siblings were 5.57 years (SD = 0.77). Each dyad (mother-older sibling, mother younger-sibling, and sibling dyad, N = 385) completed a Lego building task, and there were two directional CS scores per interaction (e.g., mother toward older sibling, and older sibling toward mother). Results from multilevel models indicated that younger siblings' vocabulary was associated with the average level of CS for mothers and older siblings, independently. Conversely, older siblings' vocabulary was associated with the average level of maternal CS and child-specific maternal CS. Findings suggest that the relationship between CS and vocabulary operates across the family system and differs for older and younger siblings. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Identification of Novel CXCL12 Genetic Polymorphisms Associated with Type 2 Diabetes Mellitus: A Chinese Sib-Pair Study.

Aims: To discover possible relationships between CXCL12 single nucleotide polymorphisms (SNPs) and type 2 diabetes mellitus (T2DM) and its risk factors. Methods: The present sib-pair study was conducted in a rural community of Beijing, China. SNPs rs2297630, rs1746048, and rs1801157 located within or nearby the CXCL12 gene were genotyped using the allele-specific polymerase chain reaction method. Haseman-Elston regression was used to investigate linkages between these SNPs and T2DM. A generalized estimating equation logistic regression model was used to discover associations between the SNPs, T2DM, and its risk factors. Results: A total of 3171 participants were recruited, comprising 2277 sib pairs. After Bonferroni correction (α = 0.016), rs2297630 was found to be significantly linked to (p = 0.003) and associated with T2DM (AA vs. GG/GA: OR = 2.26, 95% CI: 1.31-3.88, p = 0.003). There were interactions between rs2297630 and dyslipidemia (p < 0.001) and between rs1746048 and hypertension (p = 0.011). Compared to dyslipidemia-free subjects with rs2297630 GG/GA genotypes, dyslipidemia patients with rs2297630 AA had a higher risk of T2DM (OR = 4.15, 95% CI: 2.24-7.67, p < 0.001). Compared to hypertension-free subjects with rs1746048 CC genotypes, hypertension-free subjects with rs1746048 CT/TT had a decreased risk of T2DM (OR = 0.77, 95% CI: 0.60-0.99, p = 0.045). Conclusions: A novel linkage and association was found between rs2297630 and T2DM. Moreover, novel interactions were found between rs2297630 and dyslipidemia as well as rs1746048 and hypertension. These findings will help identify individuals at higher risk of developing T2DM.

Relationship estimation in affected sib pair analysis of late-onset diseases.

In linkage studies, errors in pedigree structure will often be uncovered through Mendelian inconsistencies. In affected sib pair analysis of diseases with late onset, however, such mistakes will usually go undetected since parental genotypes are commonly not known. Cases of nonpaternity, unrecorded adoption or accidental sample swap in the laboratory will then not be noticed. Typically, such relationship errors lead to a decrease in power for linkage. In this paper, a method is presented which allows verification of the relationship between stated sibs using their marker genotypes. The method is likelihood-based and incorporates a Bayesian approach to compute posterior relationship probabilities. It is shown that sibs, half-sibs and unrelated individuals can be distinguished from each other quite reliably using numbers of markers that should be available in most sib pair studies. It is demonstrated that elimination of false sib pairs increases the power to detect linkage in affected sib pair studies. The gain in power may be large if relationship errors occur quite frequently; the gain will be only moderate if relationship errors are very infrequent. Software for relationship estimation is provided.

Supplemental Material for Cognitive Sensitivity and Child Receptive Vocabulary: A Between- and Within-Family Study of Mothers and Sibling Pairs

Supplemental Material for Cognitive Sensitivity and Child Receptive Vocabulary: A Between- and Within-Family Study of Mothers and Sibling Pairs

SA109 - CROSS-SPECIES ANALYSIS OF ALCOHOL-REGULATED AND DEPENDENCE-ASSOCIATED GENE NETWORKS IN THE VENTRAL TEGMENTAL AREA

Background Despite studies suggesting that Alcohol Dependence (AD) is moderately heritable, Genome-Wide Association Studies (GWAS) on AD lack power for detecting the small contribution of individual genes to risk, and the ability to determine their mechanistic role in this complex disorder. Gene co-expression networks provide information about the mechanistic framework through which genetic variants take their effects on AD. Studying gene expression in human brains can be problematic. However, studies have identified significantly ethanol-associated gene networks in mice. Direct integration of human GWAS and Protein-Protein Interaction (PPI) data with mouse gene expression data has the potential to identify novel associated loci and the mechanistic frameworks through which they function. We therefore believe that this co-analysis will identify such loci and networks, and that these networks will reflect results of other GWAS's. Methods The present analysis used Edge-Weighted dense module searching for Genome-Wide Association Studies (EW-dmGWAS) to co-analyze GWAS data from the Irish Affected Sib-Pair Study of Alcohol Dependence, human PPI data, and acute-ethanol-exposed mouse gene expression data, to identify and prioritize ethanol-regulated gene networks (i.e. modules) with respect to AD risk contribution. Expression data was obtained from the Ventral Tegmental Area (VTA), due to its role in reward pathways, and previous findings of significantly ethanol-regulated networks in this region. To validate our results, we tested modules for overrepresentation of genes with nominal GWAS p-values from an alternative GWAS dataset (Avon Longitudinal Study of Parents and Children; ALSPAC). To determine the functional relatedness of genes within significantly overrepresented modules, we analyzed their functional enrichment using ToppGene. Finally, to specifically assess the prioritization of modules, we examined the association of module scores with ALSPAC p-values. Results Of the 276 significantly alcohol-associated modules, 25 of them contained at least one gene with nominal significance in ALSPAC. One of these modules showed significant overrepresentation of these genes, after correction for multiple testing (p=0.006). This module showed functional enrichment for genes associated with ubiquitination, abnormal glial and muscle cell morphology, and neuron degeneration. Finally, module scores was significantly, negatively associated with ALSPAC p-value (β=-2.05, p=0.003) (meaning higher module scores indicated smaller p-values). Discussion The results indicate that integration of mouse gene expression data and human genetic data via EW-dmGWAS allows identification of novel alcohol-associated gene networks in the VTA, and that the resulting scores successfully prioritize these modules with respect to association with risk for AD. This suggests that these modules are bridging the gap between the disparate results of independent GWAS's, and that some of the relevant mechanisms involve dopaminergic reward pathways relevant to the early stages of AD development. One of these modules was significantly overrepresented with nominally significant genes from that dataset, indicating that it is of particular importance. The functional enrichment of its constituent genes suggests that the Ventral Tegmental Area is associated with AD by way of alcohol-regulated pathways involving neuron degeneration via ubiquitination.

Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population-Based and Clinically Ascertained Samples.

Despite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population-based epidemiological samples. Four independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N=4,304; FinnTwin12 [FT12], N=1,135) and 2 from families densely affected with AUDs, identified from treatment-seeking patients (Collaborative Study on the Genetics of Alcoholism, N=2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N=706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery-validation pairs), and from meta-analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types. Polygenic scores derived from 1 population-based sample (ALSPAC) significantly predicted AUD symptoms in another population-based sample (FT12), but not in either clinically ascertained sample. Trend-level associations (uncorrected p<0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms. Though preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment-seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder.

Variation in SWI/SNF Chromatin Remodeling Complex Proteins is Associated with Alcohol Dependence and Antisocial Behavior in Human Populations

Testing for direct gene or single nucleotide polymorphism replication of association across studies may not capture the true importance of a candidate locus; rather, we suggest that relevant replication across studies may be found at the level of a biological process. We previously observed that variation in 2 members of the switching defective/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex is associated with alcohol dependence (AD) in the Irish Affected Sib Pair Study for Alcohol Dependence. Here, we tested for association with alcohol-related outcomes using a set of genes functioning in the SWI/SNF complex in 2 independent samples. We used a set-based analysis to examine the 29 genes of the SWI/SNF complex for evidence of association with (i) AD in the adult Collaborative Study on the Genetics of Alcoholism (COGA) case-control sample and (ii) antisocial behavior, hypothesized to be a genetically related developmental precursor, in a younger population sample (Spit for Science [S4S]). We found evidence for association of the SWI/SNF complex with AD in COGA (p=0.0435) and more general antisocial behavior in S4S (p=0.00026). The genes that contributed most strongly to the signal in COGA were SS18L1, SMARCD1, BRD7, BCL7B, SMARCB1, and BCL11A. In the S4S sample, ACTB, ARID2, BCL11A, BCL11B, BCL7B, BCL7C, DPF2, and DPF3 all contributed strongly to the signal. We detected associations between the SWI/SNF complex and AD in an adult population selected from treatment-seeking probands and antisocial behavior in an adolescent population sample. This provides strong support for a role for SWI/SNF in the development of alcohol-related problems.

Insulin Resistance Is Associated With Smaller Cortical Bone Size in Nondiabetic Men at the Age of Peak Bone Mass.

In type 2 diabetes mellitus, fracture risk is increased despite preserved areal bone mineral density. Although this apparent paradox may in part be explained by insulin resistance affecting bone structure and/or material properties, few studies have investigated the association between insulin resistance and bone geometry. We aimed to explore this association in a cohort of nondiabetic men at the age of peak bone mass. Nine hundred ninety-six nondiabetic men aged 25 to 45 years were recruited in a cross-sectional, population-based sibling pair study at a university research center. Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR), with insulin and glucose measured from fasting serum samples. Bone geometry was assessed using peripheral quantitative computed tomography at the distal radius and the radial and tibial shafts. In age-, height-, and weight-adjusted analyses, HOMA-IR was inversely associated with trabecular area at the distal radius and with cortical area, periosteal and endosteal circumference, and polar strength strain index at the radial and tibial shafts (β ≤ -0.13, P < 0.001). These associations remained essentially unchanged after additional adjustment for dual-energy X-ray absorptiometry-derived body composition, bone turnover markers, muscle size or function measurements, or adiponectin, leptin, insulin-like growth factor 1, or sex steroid levels. In this cohort of nondiabetic men at the age of peak bone mass, insulin resistance is inversely associated with trabecular and cortical bone size. These associations persist after adjustment for body composition, muscle size or function, or sex steroid levels, suggesting an independent effect of insulin resistance on bone geometry.

Associations between homocysteine metabolism related SNPs and carotid intima-media thickness: a Chinese sib pair study

Carotid intima-media thickness (CIMT) is a good surrogate for atherosclerosis. Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. We aim to investigate the relationships between homocysteine (Hcy) related biochemical indexes and CIMT, the associations between Hcy related SNPs and CIMT, as well as the potential gene–gene interactions. The present study recruited full siblings (186 eligible families with 424 individuals) with no history of cardiovascular events from a rural area of Beijing. We examined CIMT, intima-media thickness for common carotid artery (CCA-IMT) and carotid bifurcation, tested plasma levels for Hcy, vitamin B6 (VB6), vitamin B12 (VB12) and folic acid (FA), and genotyped 9 SNPs on MTHFR, MTR, MTRR, BHMT, SHMT1, CBS genes. Associations between SNPs and biochemical indexes and CIMT indexes were analyzed using family-based association test analysis. We used multi-level mixed-effects regression model to verify SNP-CIMT associations and to explore the potential gene–gene interactions. VB6, VB12 and FA were negatively correlated with CIMT indexes (p < 0.05). rs2851391 T allele was associated with decreased plasma VB12 levels (p = 0.036). In FABT, CBS rs2851391 was significantly associated with CCA-IMT (p = 0.021) and CIMT (p = 0.019). In multi-level mixed-effects regression model, CBS rs2851391 was positively significantly associated with CCA-IMT (Coef = 0.032, se = 0.009, raw p < 0.001) after Bonferoni correction (corrected α = 0.0056). Gene–gene interactions were found between CBS rs2851391 and BHMT rs10037045 for CCA-IMT (p = 0.011), as well as between CBS rs2851391 and MTR rs1805087 for CCA-IMT (p = 0.007) and CIMT (p = 0.022). Significant associations are found between Hcy metabolism related genetic polymorphisms, biochemical indexes and CIMT indexes. There are complex interactions between genetic polymorphisms for CCA-IMT and CIMT.

Gender differences in autism spectrum disorders: Divergence among specific core symptoms.

Community-based studies have consistently shown a sex ratio heavily skewed towards males in autism spectrum disorders (ASD). The factors underlying this predominance of males are largely unknown, but the way girls score on standardized categorical diagnostic tools might account for the underrecognition of ASD in girls. Despite the existence of different norms for boys and girls with ASD on several major screening tests, the algorithm of the Autism Diagnosis Interview-Revised (ADI-R) has not been reformulated. The aim of our study was to investigate which ADI-R items discriminate between males and females, and to evaluate their weighting in the final diagnosis of autism. We then conducted discriminant analysis (DA) on a sample of 594 probands including 129 females with ASD, recruited by the Paris Autism Research International Sibpair (PARIS) Study. A replication analysis was run on an independent sample of 1716 probands including 338 females with ASD, recruited through the Autism Genetics Resource Exchange (AGRE) program. Entering the raw scores for all ADI-R items as independent variables, the DA correctly classified 78.9% of males and 72.9% of females (P < 0.001) in the PARIS cohort, and 72.2% of males and 68.3% of females (P < 0.0001) in the AGRE cohort. Among the items extracted by the stepwise DA, four belonged to the ADI-R algorithm used for the final diagnosis of ASD. In conclusion, several items of the ADI-R that are taken into account in the diagnosis of autism significantly differentiates between males and females. The potential gender bias thus induced may participate in the underestimation of the prevalence of ASD in females. Autism Res 2016,. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 680-689. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Maternal age at childbirth is associated with offspring insulin sensitivity: a cross-sectional study in adult male siblings.

Maternal age at childbirth is increasing worldwide, but studies investigating the consequences of this trend on offspring metabolic health are scarce. We investigated the associations of maternal age at childbirth with metabolic outcomes in adult male siblings. We used data from 586 men aged 25-45 participating in a cross-sectional, population-based sibling-pair study, including maternal age at childbirth and offspring birthweight, adult weight, height, dual-energy X-ray absorptiometry (DXA)-derived body composition, blood pressure, and total cholesterol, glucose and insulin levels from fasting serum samples. Insulin sensitivity was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). Maternal age at childbirth was 27·1 ± 4·7 years and was inversely associated with glucose levels (β = -0·10, P = 0·022) and HOMA-IR (β = -0·06, P = 0·065) in age- and body composition-adjusted analyses. Moreover, sons of younger (aged <25 and 25-29) and older (aged ≥35) mothers had higher HOMA-IR values than sons of mothers aged 30-34 (1·39, 1·35 and 1·42 vs 1·19, P = 0·028). Additional adjustment for birthweight did not substantially alter these results. Maternal age was inversely associated with cholesterol levels in unadjusted (β = -0·09, P = 0·032), but not in age- and body composition-adjusted analyses. No associations of maternal age were observed with blood pressure, leptin, or adiponectin levels or with any of the body composition measurements. Increasing maternal age at childbirth is associated with lower fasting glucose levels and higher insulin sensitivity in adult male offspring. However, this association might not hold true in offspring of women aged ≥35 years at childbirth.

Differences in neuropsychological and behavioral parameters and brain structure in patients with familial adenomatous polyposis: a sibling-paired study.

BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant hereditary colon cancer syndrome caused by mutations in adenomatous polyposis coli (APC) with both colonic and extra-colonic manifestations. Case reports have noted an association with FAP and intellectual disability and animal studies have shown that APC is implicated in neural development and function, but no studies have investigated neuropsychological, behavioral, or structural brain characteristics of patients with FAP.MethodsWe undertook a pilot, sibling-pair study comparing three patients with FAP to their sex-matched siblings without FAP. Each sibling pair underwent neuropsychological testing by a blinded examiner, high resolution brain MRI scans, and the mother of each pair rated her children’s adaptive life skills and behavioral and emotional characteristics. Given the small number of study participants in this pilot study, quantitative comparisons of results were made by subtracting the score of the non-FAP sibling from the FAP patient on the various neuropsychological tests and parent rating questionnaires to calculate a difference, which was then divided by the standard deviation for each individual test to determine the difference, corrected for the standard deviation. Diffusion numbers in multiple regions of the brain as assessed by MRI were calculated for each study participant.ResultsWe found similarity between siblings in all three pairs on a wide range of neuropsychological measures (general intelligence, executive function, and basic academic skills) as tested by the psychologist as well as in descriptions of adaptive life skills as rated by mothers. However, mothers’ ratings of behavioral and emotional characteristics of two of the three pairs showed differences between the siblings, specifically that the patients with FAP were found to have more behavioral and emotional problems compared to their siblings. No differences in brain structure were identified by MRI.ConclusionWe report the first study exploring neuropsychological, behavioral, emotional, and structural brain characteristics of patients with FAP and found subjective differences as assessed by maternal perception in behavioral and emotional characteristics in patients with FAP compared to their siblings. Larger studies are needed to elucidate the relationship, if any, between FAP and brain function.

Maternal smoking during pregnancy and offspring’s tobacco dependence. A study of exposure-discordant sibling pairs

BackgroundPrenatal exposure to maternal smoking has previously been linked to tobacco dependence, but confounding from genetic and early-environmental factors is of concern. The aim of this study was to clarify if maternal smoking during pregnancy may affect the onset and manifestations of tobacco dependence after taking such factors into account. MethodsThe study is based on a matched cohort of 1538 siblings discordant for prenatal exposure to maternal smoking, who participated in a survey conducted in 2010 in Sweden. Analyses were based on pairs where both siblings had been daily smokers (193 pairs) or snus users (173 pairs) at some time in their life. Participants were 19–27 years old at the time of participation. Outcomes were tobacco dependence measured with the Cigarette Dependence Scale (CDS-12) in smokers and with the adapted Smokeless Tobacco Dependence Scale (STDS-12) in snus users, and previous quit attempts. Exposure to maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register. ResultsThere was no difference in dependence scores in exposure-discordant siblings (mean difference 0.36 on CDS-12 [95% confidence interval: −1.23 to 1.95] and 0.61 on STDS-12 [95% confidence interval: −1.20 to 2.43]). Neither did the siblings differ with regard to previous quit attempts. ConclusionsMaternal smoking during pregnancy does not appear to influence tobacco dependence in adult offspring. A potential effect of heavy maternal smoking during pregnancy cannot be excluded, but genetic and environmental influences seem to be more influential for the onset of tobacco dependence.