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Objective: Pancreatic beta cell destruction is a hallmark of type 1 diabetes (T1D), a heterogeneous disorder with a wide range of potential causes. T cell activation molecules have been shown to play an important role in the development of T1D, according to the majority of studies. Some autoimmune diseases have been linked to SNPs in the 4q27 region, specifically in the KIAA1109-interleukin 2 (IL2)-IL21 block. The purpose of this research was to look into how certain polymorphic variants in the 4q27 region are linked to T1D. Methods: We investigated whether variants in the 4q27 region could be a causal factor in T1D susceptibility. Polymorphisms of ten single-nucleotide polymorphisms (SNPs) belonging to the KIAA1109/IL21/IL2 block were studied in 255 individuals from 59 families using the Sequenom MassARRAY platform. Results: The IL21/IL2 region was found to have a significant association with T1D in Tunisian cohorts. We found that the T allele of the rs2221903 marker is disproportionately passed down from parents to their children. In addition, haplotype analyses encompassing all of the SNPs under consideration show that the GACAGGA and the shortly TT haplotypes were significantly over-transmitted from parents to their children, suggesting they may be a T1D genetic susceptibility factor in our population. Conclusion: Several autoimmune disorders (ADs) have been linked to the IL2/IL21 genes, suggesting that there is a shared genetic background that confers a common genetic predisposition across ADs. More research into the genetic and functional aspects of the 4q27 region is needed to better explain the role it plays in the risk of ADs. [ABSTRACT FROM AUTHOR]

Background. Pre-fire fuels, topography, and weather influence wildfire behaviour and firedriven ecosystem carbon loss. However, the pre-fire characteristics that contribute to fire behaviour and effects are often understudied for wildfires because measurements are difficult to obtain. Aims. This study aimed to investigate the relative contribution of pre-fire conditions to fire energy and the role of fire advancement direction in fuel consumption. Methods. Over 15 years, we measured vegetation and fuels in California mixed-conifer forests within days before and after wildfires, with co-located measurements of active fire behaviour. Key results. Pre-fire litter and duff fuels were the most important factors in explaining fire energy and contributed similarly across severity categories. Consumption was greatest for the forest floor (litter and duff; 56.8 Mg ha-1) and 1000-h fuels (36.0 Mg ha-1). Heading fires consumed 13.2 Mg ha-1 more litter (232%) and 24.3 Mg ha-1 more duff (202%) than backing fires. Remotely sensed fire severity was weakly correlated (R2 = 0.14) with fuel consumption. Conclusions. 1000-h fuels, litter, and duff were primary drivers of fire energy, and heading fires consumed more fuel than backing fires. Implications. Knowledge of how consumption and fire energy differ among contrasting types of fire behaviours may inform wildfire management and fuels treatments. [ABSTRACT FROM AUTHOR]

Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable and prevalent neurodevelopmental disorder that frequently persists into adulthood. Strong evidence from genetic studies indicates that single nucleotide polymorphisms (SNPs) harboured in the ADGRL3 (LPHN3), SNAP25, FGF1, DRD4, and SLC6A2 genes are associated with ADHD. We genotyped 26 SNPs harboured in genes previously reported to be associated with ADHD and evaluated their potential association in 386 individuals belonging to 113 nuclear families from a Caribbean community in Barranquilla, Colombia, using family-based association tests. SNPs rs362990-SNAP25 (T allele; p = 2.46 × 10−4), rs2282794-FGF1 (A allele; p = 1.33 × 10−2), rs2122642-ADGRL3 (C allele, p = 3.5 × 10−2), and ADGRL3 haplotype CCC (markers rs1565902-rs10001410-rs2122642, OR = 1.74, Ppermuted = 0.021) were significantly associated with ADHD. Our results confirm the susceptibility to ADHD conferred by SNAP25, FGF1, and ADGRL3 variants in a community with a significant African American component, and provide evidence supporting the existence of specific patterns of genetic stratification underpinning the susceptibility to ADHD. Knowledge of population genetics is crucial to define risk and predict susceptibility to disease.

Mitochondrial dysfunction has been reported to be involved in the pathophysiology of autism spectrum disorder (ASD). Studies investigating the possible association between ASD and polymorphism in SLC25A12, which encodes the mitochondrial aspartate/glutamate carrier, have yielded inconsistent results. We conducted a systematic review and meta-analysis of such studies to elucidate if and which SLC25A12 single nucleotide polymorphisms (SNPs) are associated with ASD. We searched PubMed, Ovid, Web of Science, and ERIC databases through September 20th, 2014. Odds ratios (ORs) were aggregated using random effect models. Sensitivity analyses were conducted based on study design (family-based or case-control). Fifteen out of 79 non-duplicate records were retained for qualitative synthesis. We pooled 10 datasets from 9 studies with 2001 families, 735 individuals with ASD and 632 typically developing (TD) individuals for the meta-analysis of rs2292813, as well as 11 datasets from 10 studies with 2016 families, 852 individuals with ASD and 1058 TD individuals for the meta-analysis of rs2056202. We found a statistically significant association between ASD and variant in rs2292813 (OR = 1.190, 95 % CI 1.052-1.346, P = 0.006) as well as in rs2056202 (OR = 1.206, 95 % CI 1.035-1.405, P = 0.016). Sensitivity analyses including only studies with family-based design demonstrated significant association between ASD and polymorphism in rs2292813 (OR = 1.216, 95 % CI 1.075-1.376, P = 0.002) and rs2056202 (OR = 1.267, 95 % CI 1.041-1.542, P = 0.018). In contrast, sensitivity analyses including case-control design studies only failed to find a significant association. Further research on the role of SLC25A12 and ASD may pave the way for potential innovative therapeutic interventions. [ABSTRACT FROM AUTHOR]

BACKGROUND The forkhead box F2 gene ( FOXF2) located in chromosome 6p25.3 has been shown to play a crucial role in palatal development in mouse and rat models. To date, no evidence of linkage or association has been reported for this gene in humans with oral clefts. METHODS Allelic transmission disequilibrium tests were used to robustly assess evidence of linkage and association with nonsyndromic cleft lip with or without cleft palate for nine single nucleotide polymorphisms (SNPs) in and around FOXF2 in both Asian and European trios using PLINK. RESULTS Statistically significant evidence of linkage and association was shown for two SNPs ( rs1711968 and rs732835) in 216 Asian trios where the empiric P values with permutation tests were 0.0016 and 0.005, respectively. The corresponding estimated odds ratios for carrying the minor allele at these SNPs were 2.05 (95% confidence interval = 1.41, 2.98) and 1.77 (95% confidence interval = 1.26, 2.49), respectively. CONCLUSION Our results provided statistical evidence of linkage and association between FOXF2 and nonsyndromic cleft lip with or without cleft palate. Birth Defects Research (Part A) 103:857-862, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Although transmission disequilibrium tests (TDT) and the FBAT statistic are robust against population substructure, they have reduced statistical power, as compared with fully efficient tests that are not guarded against confounding because of population substructure. This has often limited the application of transmission disequilibrium tests/FBATs to candidate gene analysis, because, in a genome-wide association study, population substructure can be adjusted by approaches such as genomic control and EIGENSTRAT. Here, we provide new statistical methods for the analysis of quantitative and dichotomous phenotypes in extended families. Although the approach utilizes the polygenic model to maximize the efficiency, it still preserves the robustness to non-normality and misspecified covariance structures. In addition, the proposed method performs better than the existing methods for dichotomous phenotype, and the new transmission disequilibrium test for candidate gene analysis is more efficient than FBAT statistics. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Leptin (LEP) gene is one of the most promising candidate genes for obesity. Previous studies have tested the association of polymorphisms in LEP gene with obesity and obesity-related metabolic biomarkers (anthropometric variables, glucose, insulin level, leptin level and lipid profile). However, the results of these studies were still controversial. To determine whether LEP gene is associated with obesity in Tunisian population, we performed a family-based association study between LEP polymorphisms and obesity and obesity-related metabolic biomarkers. Methods: Seven single nucleotide polymorphisms (SNPs) in 5′ region of LEP gene were genotyped in three consanguineous families including 33 individuals. The previously reported LEP SNPs (H1328084, H1328082, rs10487506, H1328081, H1328080, G-2548A and A19G) were evaluated by PCR-RFLP and direct sequencing methods. Single SNP association and haplotype association analyses were performed using the family-based association test (FBAT). To determine allele frequencies of these SNPs in general population, 52 unrelated individuals from the general Tunisian population were also analyzed. Results: Two SNPs showed significant associations with plasma leptin level (H1328084: A>G, Z=2.058, p =0.039; A19G: G>A, Z=2.058, p =0.039). When haplotypes were constructed with these two-markers, the risk AA haplotype (frequency 57.1%) was positively associated with plasma leptin level (Z=2.058, p =0.039). Moreover, SNPs H1328084 and A19G are predicted to modify transcription-factor binding sites. Conclusions: Our study provided that two functional variants in 5′ regulatory region of LEP gene are associated with plasma leptin level as a quantitative trait. It suggested that H1328084 and A19G have an important role in regulating plasma leptin level. [Copyright &y& Elsevier]

Background: Few studies have examined the effect of the angiotensin II type I receptor (AT1R) A1166C polymorphism on the antihypertensive effect of the angiotensin-converting-enzyme inhibitor benazepril in patients with hypertension, and no such studies have performed analysis using the Family-Based Association Test (FBAT), The aim of our study was to examine the association between AT1R A1166C gene polymorphism and the antihypertensive effect of benazepril using the FBAT. Methods and Results: A total of 864 patients (aged, 26-62 years) with essential hypertension were identified in an epidemiological survey and enrolled in this study. Blood pressure (BP) was measured before and after 16 days of treatment with benazepril (10 mg/day). The association between the A1166C gene polymorphism and the antihypertensive effect of benazepril was assessed by FBAT. The frequencies of alleles A and C were 95.1% and 4.9%, respectively. FBAT analysis revealed that the C allele was significantly associated with high baseline diastolic BP (Z = 2.041, p = 0.041), decreased systolic BP after treatment (Z = 2.549, p = 0.011), and decreased diastolic BP after treatment (Z = 2.320, p = 0.020). Conclusion: Our results, determined using the FBAT, are the first evidence that the AT1R A1166C polymorphism may increase the antihypertensive effect of benazepril in patients with hypertension. [ABSTRACT FROM AUTHOR]

Identifying the risk factors for mental illnesses is of significant public health importance. Diagnosis, stigma associated with mental illnesses, comorbidity, and complex etiologies, among others, make it very challenging to study mental disorders. Genetic studies of mental illnesses date back at least a century ago, beginning with descriptive studies based on Mendelian laws of inheritance. A variety of study designs including twin studies, family studies, linkage analysis, and more recently, genomewide association studies have been employed to study the genetics of mental illnesses, or complex diseases in general. In this paper, I will present the challenges and methods from a statistical perspective and focus on genetic association studies. [ABSTRACT FROM AUTHOR]

Despite its high heritability, genetic association studies of attention deficit-hyperactivity disorder (ADHD) have often resulted in somewhat small, inconsistent effects. Refining the ADHD phenotype beyond a dichotomous diagnosis and testing associations with continuous information from the underlying symptom dimensions may result in more consistent genetic findings. This study further examined the association between ADHD and the DRD4, DAT1, and 5HTT genes by testing their association with multivariate phenotypes derived from continuous measures of ADHD symptom severity. DNA was collected in 202 families consisting of at least one ADHD proband and at least one parent or sibling. VNTR polymorphisms of the DRD4 and DAT1 genes were significantly associated with the continuous ADHD phenotype. The association with DRD4 was driven by both inattentive and hyperactive symptoms, while the association with DAT1 was driven primarily by inattentive symptoms. These results use novel methods to build upon important connections between dopamine genes and their final behavioral manifestation as symptoms of ADHD. [ABSTRACT FROM AUTHOR]

Background: Disrupted-in-Schizophrenia 1 (DISC1) gene is one of the most promising candidate genes for major mental disorders. In a previous study, a Finnish group demonstrated that DISC1 polymorphisms were associated with autism and Asperger syndrome. However, the results were not replicated in Korean population. To determine whether DISC1 is associated with autism in Chinese Han population, we performed a family-based association study between DISC1 polymorphisms and autism. Methods: We genotyped seven tag single nucleotide polymorphisms (SNPs) in DISC1, spanning 338 kb, in 367 autism trios (singleton and their biological parents) including 1,101 individuals. Single SNP association and haplotype association analysis were performed using the family-based association test (FBAT) and Haploview software. Results: We found three SNPs showed significant associations with autism (rs4366301: G > C, Z = 2.872, p = 0.004; rs11585959: T > C, Z = 2.199, p = 0.028; rs6668845: A > G, Z = 2.326, p = 0.02). After the Bonferroni correction, SNP rs4366301, which located in the first intron of DISC1, remained significant. When haplotype were constructed with two-markers, three haplotypes displayed significant association with autism. These results were still significant after using the permutation method to obtain empirical p values. Conclusions: Our study provided evidence that the DISC1 may be the susceptibility gene of autism. It suggested DISC1 might play a role in the pathogenesis of autism. [ABSTRACT FROM AUTHOR]

Background: Human craniofacial morphology is characterized by considerable diversity among individuals. The ENPP1 gene is essential for bone physiology. However, the potential effects of its genetic variants on head size phenotypes have not yet been studied. Aim: The aim of this research was to investigate the association of polymorphisms in the ENPP1 locus with normal variability of craniofacial phenotypes. Subjects and methods: Fourteen SNPs and 13 haplotypes in the ENPP1 locus were tested for association with six head size traits in 1042 Western Eurasian individuals. Results: The most significant and consistent association was observed between upper facial height and the polymorphisms located near the promoter region and upstream from ENPP1 gene ( p = 0.00009), which remained significant after adjustment for multiple testing. Additionally, association signals were detected between head breadths and lower face height, and markers residing in or close to the promoter and 3′ untranslated regions of the ENPP1 gene ( p < 0.05). Conclusions: The findings obtained in this study suggest that the upstream, promoter and 3′ untranslated regions in the ENPP1 locus harbor genetic variants affecting different aspects of craniofacial morphology. Further research is required to validate the relevancy of the potentially functional ENPP1 regions to normal and pathologic craniofacial growth. [ABSTRACT FROM AUTHOR]

To identify genetic factors that influence height in infancy/early childhood , a family-based genome-wide association study was conducted using 269 888 single-nucleotide polymorphisms (SNPs) in 165 families composed of a Korean father, a Vietnamese mother and Vietnamese-Korean offspring in the International Marriage-based Immigrant Cohort in Korea. In a single-SNP-based analysis, the six SNPs in or near genes MAF, MAGI2, BMP4 and PTPN7 showed consistent suggestive associations at all height standard deviation scores using Korean, World Health Organization and Vietnamese growth references. Analyzing the haplotypes for the genes, haplotype blocks were found to be significantly associated with height. Similar to the results of a contiguous haplotype analysis using tag SNPs as above, noncontiguous haplotypes of variable length also showed a significant association near the suspected loci. Our result suggests that height during infancy/early childhood may be regulated by genetic variations that differ from those of adults. [ABSTRACT FROM AUTHOR]

Abstract: Mineralization of the extracellular matrix of bone is an essential element of bone development, maintenance and repair. ALPL and ENPP1 genes and their products are known to be central in local regulation of bone mineralization. The present study investigates potential associations of ENPP1 and ALPL polymorphisms with several phenotypes reflecting bone size and hand BMD. The study sample included 310 Caucasian nuclear families. Forty SNPs in ALPL and 14 SNPs in ENPP1 genetic loci as well as pairwise haplotypes were tested for association with bone strength related traits. Our findings suggest that the region corresponding to exons 7 through 9 of the ALPL gene harbors functional polymorphism affecting both bone size at various skeletal sites (p-value ranged from 0.01 to 0.0001) and hand bone mineral density (p-value=0.0007). The other important finding of consistent association between bone size phenotypes and the 3′ untranslated region of ENPP1 gene (p-value ranged from 0.01 to 0.001) imply functional significance of this region to bone growth. The considered anthropometric and radiographic bone phenotypes are closely related to bone fragility thus suggesting a role for both genes in osteoporosis. Further research is required to validate the relevancy of the potentially functional regions identified by our and other studies to normal and pathologic bone development as well as to determine the relevancy of the polymorphisms in ALPL and ENPP1 gene loci to clinical practice. [Copyright &y& Elsevier]

Genome-Wide Association Studies (GWAS) offer an exciting and promising new research avenue for finding genes for complex diseases. Traditional case-control and cohort studies offer many advantages for such designs. Family-based association designs have long been attractive for their robustness properties, but robustness can mean a loss of power. In this paper we discuss some of the special features of family designs and their relevance in the era of GWAS. [ABSTRACT FROM AUTHOR]

For genome-wide association studies in family-based designs, a new, universally applicable approach is proposed. Using a modified Liptak’s method, we combine the p-value of the family-based association test (FBAT) statistic with the p-value for the Van Steen-statistic. The Van Steen-statistic is independent of the FBAT-statistic and utilizes information that is ignored by traditional FBAT-approaches. The new test statistic takes advantages of all available information about the genetic association, while, by virtue of its design, it achieves complete robustness against confounding due to population stratification. The approach is suitable for the analysis of almost any trait type for which FBATs are available, e.g. binary, continuous, time-to-onset, multivariate, etc. The efficiency and the validity of the new approach depend on the specification of a nuisance/tuning parameter and the weight parameters in the modified Liptak’s method. For different trait types and ascertainment conditions, we discuss general guidelines for the optimal specification of the tuning parameter and the weight parameters. Our simulation experiments and an application to an Alzheimer study show the validity and the efficiency of the new method, which achieves power levels that are comparable to those of population-based approaches. [ABSTRACT FROM AUTHOR]

Several family-based approaches have been previously proposed to enhance the power for testing genetic association when the traits are measured longitudinally or repeatedly. In this paper, we show that some of these FBAT approaches can be easily extended to accommodate incomplete data and remain unbiased tests. We also show that because of the nature of FBAT approaches, we can impute the missing phenotypes without biasing our tests and achieve higher power. We propose two imputation techniques based on E-M algorithm and the conditional mean model, respectively. Through simulation studies, these two imputation techniques are shown to have correct false positive rate and generally achieve higher power than complete case analysis or simple mean-imputation. Application of these approaches for testing an association between Body Mass Index and a previously reported candidate SNP confirms our results. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The transmission disequilibrium test (TDT) is a standard method to detect association using family trio design. It is optimal for an additive genetic model. Other TDT-type tests optimal for recessive and dominant models have also been developed. Association tests using family data, including the TDT-type statistics, have been unified to a class of more comprehensive and flexable family-based association tests (FBAT). TDT-type tests have high efficiency when the genetic model is known or correctly specified, but may lose power if the model is mis-specified. Hence tests that are robust to genetic model mis-specification yet efficient are preferred. Constrained likelihood ratio test (CLRT) and MAX-type test have been shown to be efficiency robust. In this paper we propose a new efficiency robust procedure, referred to as adaptive TDT (aTDT). It uses the Hardy-Weinberg disequilibrium coefficient to identify the potential genetic model underlying the data and then applies the TDT-type test (or FBAT for general applications) corresponding to the selected model. Simulation demonstrates that aTDT is efficiency robust to model mis-specifications and generally outperforms the MAX test and CLRT in terms of power. We also show that aTDT has power close to, but much more robust, than the optimal TDT-type test based on a single genetic model. Applications to real and simulated data from Genetic AnalysisWorkshop (GAW) illustrate the use of our adaptive TDT. [ABSTRACT FROM AUTHOR]

Objective: Develop a new test for family-based association studies and continuous traits that incorporates power- enhancing techniques from two existing testing strategies. Methods: The new procedure initiates with an extraction of the relevant information from the variability of the genotypes and an assessment of the approximate individual markers effects and their directions. This information is incorporated in the construction of the actual test statistic through a selection of a data-determined number of optimal linear combinations of the offspring genotypes which, in a power enhancing step, are consequently combined into a single degree of freedom test. We conduct a comparison simulation study in which the performance of the new test is contrasted with the test that is currently known to offer the highest overall power, FBAT-LC. Results: The new test has an overall performance very similar to that of FBAT-LC but attains higher power in candidate genes with lower average pairwise correlations and moderate to high allele frequencies with large gains (up to 80%) for some of the analyzed genes possessing the above-mentioned characteristics. Conclusion: The new test is a promising tool for candidate gene studies with substantial power gains for genes that are characterized by SNPs with low mean pairwise correlation. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Several lines of evidence from neuroimaging, pharmacology and genetics support the involvement of the dopaminergic system in the etiology of Attention Deficit Hyperactivity Disorder (ADHD). Previous candidate gene studies have investigated the association between a dinucleotide (CA)n repeat polymorphism, located 18.5kb from the start codon of the DRD5 gene, and ADHD. Association between the 148bp allele and ADHD has been reported in some studies, however replication of the finding has not been consistent. We tested for an association between the (CA)n repeat and adult ADHD in a sample comprised of 119 families with adult ADHD probands and 88 unrelated adult ADHD cases with a corresponding number of controls matched for age, ethnicity and sex. In the family sample we found a non-significant trend for association between the 148bp allele and ADHD (Z =1.91, p =0.055). An excess of non-transmissions was detected for the 150 and 152bp alleles (Z =−2.26, p =0.023; Z =−2.20, p =0.028). Quantitative analysis performed using the Brown Attention Deficit Disorder Scale (BADDS) showed association between the 150bp allele and lower total score (p =0.011), and lower effort (p =0.008), activation (p =0.008) and attention (p =0.01) cluster scores. We did not replicate association findings in the case–control group, likely due to the lack of statistical power of this sample. Our findings add to the literature suggesting DRD5 (CA)n repeat has a modest effect in modulating susceptibility to adult ADHD but further studies are required. [Copyright &y& Elsevier]

Abstract: Despite the importance of behavioural and environmental risk factors, there are arguments consistent with the existence of a genetic susceptibility to human African trypanosomiasis (HAT). A candidate gene association study was conducted in the Democratic Republic of Congo using a family-based sample which included a total of 353 subjects (86 trios; one case and parents (n =258) and 23 families with more than one case and parents (n =95)). Polymorphisms located on the IL1α, IL4, IL6, IL8, IL10, TNFα and IFNγ genes were genotyped after re-sequencing of the genes for extensive SNP search. The T allele of the IL6 4339 SNP was significantly associated with a decreased risk of developing the disease (p =0.0006) and a suggestive association was observed for the IL1α 5417 T SNP and an increased risk of developing the disease. These results suggest that genetic variability of the IL6 and to a lesser extent the IL1α gene are involved in the development of HAT. For the TNFα and IL10 gene polymorphisms, association results obtained here were different from those we observed in another population living under different epidemiologic conditions. This underlines the complexity of the interactions existing between host genetic polymorphisms, parasite diversity and behavioural and environmental risk factors in HAT. [Copyright &y& Elsevier]

Cholinergic dysfunction is one of the hypotheses for the cognitive deficits of schizophrenia. Neurocognitive deficits, which are well-described clinical features of schizophrenia, may be remediated by nicotine; therefore investigations of nicotinic receptor subtypes is of considerable clinical interest. We typed polymorphisms in CHRNA4 and CHRNB2 genes controlling the expression of neuronal high-affinity nicotinic receptors in 117 Canadian families having at least one schizophrenic patient. Using a family-based association strategy, we performed allele, haplotype and interaction analysis of these two loci. In the families tested, the two cholinergic genes interact to affect schizophrenia in combination ( P=0.010), while neither was sufficient alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRNA4 gene combined with CHRNB2 receptor gene may be linked to schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine whether SNPs within the dopamine transporter gene (DAT) are associated with quantitative phenotypes generated from drug frequency variables in an ADHD sample. Method: 35 SNPs were genotyped in and around DAT. We developed a quantitative phenotype at each SNP by weighting the drug frequency variables. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, a screening procedure was used to select and test the SNPs with the greatest power to detect an association in DAT. Results: No SNPs in DAT were associated with the quantitative phenotypes generated from the drug frequency variables after the multiple comparisons adjustment; however, some SNPs achieved nominal significance. A sliding window of analysis of 3 SNPs also resulted in only nominal associations. Conclusions: SNPs in DAT do not appear to be associated with the phenotypes generated from drug frequency variables among individuals with ADHD. [Copyright &y& Elsevier]

BACKGROUND:The phospholipid transfer protein (PLTP) may play a role in body fat regulation.OBJECTIVE:To investigate the association between PLTP genetic variants and obesity-related phenotypes.METHODS:Two intronic variants, one in intron 1 (c.−87G>A) and the other in intron 12 (c.1175+68T>G), were genotyped in 811 participants of the Québec Family Study. Nine obesity-related phenotypes were investigated, including body mass index (BMI), obesity (BMI≥30 kg/m2), and waist circumference, percentage of fat, fat mass and fat-free mass measured by hydrostatic weighing as well as total, visceral and subcutaneous abdominal adipose tissue areas assessed by computed tomography. Single markers and haplotypes were tested for associations in family-based designs using the FBAT program.RESULTS:The SNP located in intron 1 showed significant associations with obesity, BMI, waist circumference and fat-free mass (P<0.05). The low-frequency allele (A allele) was associated with higher trait values, suggesting that the transmission of this allele is associated with an increased risk of being obese. Significant associations were observed between haplotypes and obesity, waist circumference, percentage of fat and fat-free mass (P<0.05). The transmission of the AT haplotype (frequency=0.180) was positively associated with obesity-related phenotypes. After sequencing the promoter and the coding regions of the PLTP gene, we were unable to identify a mutation that could replicate these results.CONCLUSION:Intronic variants of the PLTP gene are significantly associated with obesity-related phenotypes. Considering the number and the relevance of candidate genes surrounding the PLTP locus and the absence of missense polymorphisms in the coding region, the associations could be mediated by a second gene allele in linkage disequilibrium with the marker locus.International Journal of Obesity (2005) 29, 1338–1345. doi:10.1038/sj.ijo.0803010; published online 7 June 2005 [ABSTRACT FROM AUTHOR]

Genome-scans performed in schizophrenia families have provided evidence for region 6p24-21 where variability may confer susceptibility to schizophrenia. Recent studies have implicated that gene DTNBP1 (dysbindin) in this region is strongly associated with schizophrenia. In a family based association study we investigated three markers located in the untranslated region of the DTNBP1 gene: rs909706, rs1047631 and rs742106. The sample size of our study is 117 families. No biased transmission towards the disorder was detected by haplotype analysis using TRANSMIT. [ABSTRACT FROM AUTHOR]

DYX1C1: was recently identified as a candidate gene for developmental dyslexia, which is characterized by an unexpected difficulty in learning to read and write despite adequate intelligence, motivation, and education. It will be important to clarify, whether the phenotype caused by DYX1C1 extends to other language-related or comorbid disorders. Impaired language development is one of the essential features in autism. Therefore, we analyzed the allelic distribution of the DYX1C1 gene by family-based association method in 100 Finnish autism families. No evidence for association was observed with any intragenic marker or with haplotypes constructed from alleles of several adjacent markers. No evidence for deviated allelic diversity was either observed: the frequency of expected dyslexia risk haplotype was comparable to its frequency in Finnish controls. Thus it seems unlikely that DYX1C1 gene would be involved in the genetic etiology of autism in Finnish patients.European Journal of Human Genetics (2005) 13, 127-130. doi:10.1038/sj.ejhg.5201272 Published online 6 October 2004 [ABSTRACT FROM AUTHOR]

FKBP1B belongs to immunophilins superfamily and functions as a cytosolic receptor protein of FK506. The role of FKBP1B in the immunosuppressive pathway of FK506 is well established. Previously, we reported a strong evidence of linkage between D2S171 microsatellite marker (located in vicinity of FKBP1B gene) and susceptibility to autoimmune thyroid diseases (AITDs). In this study, we report linkage disequilibrium between the dimorphism (C/T) in the 3′ untranslated region (3′ UTR) of FKBP1B gene and susceptibility to AITDs. DNAs were extracted from a large Tunisian family affected with Graves' disease (GD) and Hashimoto's thyroiditis (HT) and analysed by PCR-RFLP using DraIII restriction enzyme. Our results showed an excess of transmission of the allele C from heterozygous parents to affected offspring (transmission disequilibrium test (TDT)=4.76; p =0.012 ). This suggests a linkage disequilibrium of 3′ UTR (C/T) SNP with AITDs. Moreover, The FBAT analysis gives a significant association with the C allele under the recessive model ( χ 2 =5.50; p =0.018 ). These results support the involvement of FKBP1B gene in the genetic susceptibility to the AITDs development in the studied family. [ABSTRACT FROM AUTHOR]

Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable and prevalent neurodevelopmental disorder that frequently persists into adulthood. Strong evidence from genetic studies indicates that single nucleotide polymorphisms (SNPs) harboured in the ADGRL3 (LPHN3), SNAP25, FGF1, DRD4, and SLC6A2 genes are associated with ADHD. We genotyped 26 SNPs harboured in genes previously reported to be associated with ADHD and evaluated their potential association in 386 individuals belonging to 113 nuclear families from a Caribbean community in Barranquilla, Colombia, using family-based association tests. SNPs rs362990-SNAP25 (T allele; p = 2.46 × 10−4), rs2282794-FGF1 (A allele; p = 1.33 × 10−2), rs2122642-ADGRL3 (C allele, p = 3.5 × 10−2), and ADGRL3 haplotype CCC (markers rs1565902-rs10001410-rs2122642, OR = 1.74, Ppermuted = 0.021) were significantly associated with ADHD. Our results confirm the susceptibility to ADHD conferred by SNAP25, FGF1, and ADGRL3 variants in a community with a significant African American component, and provide evidence supporting the existence of specific patterns of genetic stratification underpinning the susceptibility to ADHD. Knowledge of population genetics is crucial to define risk and predict susceptibility to disease. [ABSTRACT FROM AUTHOR]

Background: A positional cloning study of bronchial hyper-responsiveness (BHR) at the 17p11 locus in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families showed significant interaction between early-life environmental tobacco smoke (ETS) exposure and genetic variants located in DNAH9 . This gene encodes the heavy chain subunit of axonemal dynein, which is involved with ATP in the motile cilia function.Our goal was to identify genetic variants at other genes interacting with ETS in BHR by investigating all genes belonging to the ' ATP-binding ' and ' ATPase activity ' pathways which include DNAH9, are targets of cigarette smoke and play a crucial role in the airway inflammation., Methods: Family-based interaction tests between ETS-exposed and unexposed BHR siblings were conducted in 388 EGEA families. Twenty single-nucleotide polymorphisms (SNP) showing interaction signals (p ≤ 5.10 -3 ) were tested in the 253 Saguenay-Lac-Saint-Jean (SLSJ) families., Results: One of these SNPs was significantly replicated for interaction with ETS in SLSJ families (p=0.003). Another SNP reached the significance threshold after correction for multiple testing in the combined analysis of the two samples (p=10 -5 ). Results were confirmed using both a robust log-linear test and a gene-based interaction test., Conclusion: The SNPs showing interaction with ETS belong to the ATP8A1 and ABCA1 genes, which play a role in the maintenance of asymmetry and homeostasis of lung membrane lipids., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

For family-based association studies, Horvath et al. proposed an algorithm for the association analysis between haplotypes and arbitrary phenotypes when the phase of the haplotypes is unknown, that is, genotype data is given. Their approach to haplotype analysis maintains the original features of the TDT/FBAT-approach, that is, complete robustness against genetic confounding and misspecification of the phenotype. The algorithm has been implemented in the FBAT and PBAT software package and has been used in numerous substantive manuscripts. Here, we propose a simplification of the original algorithm that maintains the original approach but reduces the computational burden of the approach substantially and gives valuable insights regarding the conditional distribution. With the modified algorithm, the application to whole-genome sequencing (WGS) studies becomes feasible; for example, in sliding window approaches or spatial-clustering approaches. The reduction of the computational burden that our modification provides is especially dramatic when both parental genotypes are missing. For example, for eight variants and 441 nuclear families with mostly offspring-only families, in a WGS study at the APOE locus, the running time decreased from approximately 21 hr for the original algorithm to 0.11 sec after our modification., (© 2017 WILEY PERIODICALS, INC.)

Objective: To examine the association between functional haplotypes in the catechol-o-methyltransferase (COMT) gene and ADHD diagnosis, and executive function (EF) in children with ADHD., Method: COMT single nucleotide polymorphism (SNPs; rs6269, rs4633, rs4818, and rs4680) were genotyped in 445 ADHD children. EF was assessed using Wisconsin Card Sorting Test (WCST), Tower of London, and self-ordered pointing task. COMT haplotypes were tested for association using family-based association testing (fBAT) and quantitative trait analyses., Results: fBAT analysis showed no association between COMT alleles/haplotypes and ADHD diagnosis and EF parameters. Using ANCOVA in the Caucasian only sample, significant associations between COMT haplotypes, and WCST indices were observed. However, after correction for multipletesting, the only significant effect observed was between rs6269 and the number of categories completed (a measure of concept formation ability) on the WCST, F(1,285) = 8.92, p = .003., Conclusion: These results tentatively implicate COMT gene in modulating EF in children with ADHD.

Objective: Our purpose was to determine associations between HLA alleles and psoriatic arthritis (PsA)., Methods: 678 PsA cases and 688 healthy controls were analyzed in a case-control design. The difference in the proportion of cases and controls with at least 1 copy of HLA alleles were tested for significance using χ(2) test and Fisher's exact test. Association analyses of haplotypes inferred by the Expectation-Maximization algorithm were performed. In the family-based association study, data from 283 families were analyzed., Results: Univariate analysis revealed that cases were more likely to be carriers of HLA-C*01, -C*02, -C*06, -C*12, -B*27, -B*38 and -B*57, whereas controls were more likely to be carriers of HLA-C*03, -C*07, -B*07, -B*51, -DRB1*15 and -DQB1*0602. In haplotype analyses, PsA cases were more likely to be carriers of the HLA haplotypes -C*01/-B*27, -C*02/-B*27, -C*12/-B*38, and -C*06/-B*57, while controls were more likely to be carriers of the haplotypes -C*07/-B*07 and -C*15/-B*51. In the family-based association analysis, the HLA alleles -A*02, -B*27 and -DRB1*07 were preferentially transmitted to cases, whereas the alleles -A*03, -A*28, -B*51, -DRB1*11 and -DQB1*0301 were under transmitted., Conclusion: This large case-control and family based association study shows that HLA-C*12/B*38, HLA-B*27 and HLA-C*06/B*57 are haplotypes (alleles) robustly associated with PsA. However, since patients with PsA also have psoriasis it is difficult to determine whether the primary association is with arthritis or psoriasis., (Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)