Heritability and genome-wide linkage scan of subjective happiness

Causes of individual differences in happiness, as assessed with the Subjective Happiness Scale, are investigated in a large of sample twins and siblings from the Netherlands Twin Register. Over 12,000 twins and siblings, average age 24.7 years (range 12 to 88), took part in the study. A genetic model with an age by sex design was fitted to the data with structural equation modeling in Mx. The heritability of happiness was estimated at 22% for males and 41% in females. No effect of age was observed. To identify the genomic regions contributing to this heritability, a genome-wide linkage study for happiness was conducted in sibling pairs. A subsample of 1157 offspring from 441 families was genotyped with an average of 371 micro-satellite markers per individual. Phenotype and genotype data were analyzed in MERLIN with multipoint variance component linkage analysis and age and sex as covariates. A linkage signal (logarithm of odds score 2.73, empirical p value 0.095) was obtained at the end of the long arm of chromosome 19 for marker D19S254 at 110 cM. A second suggestive linkage peak was found at the short arm of chromosome 1 (LOD of 2.37) at 153 cM, marker D1S534 (empirical p value of .209). These two regions of interest are not overlapping with the regions found for contrasting phenotypes (such as depression, which is negatively associated with happiness). Further linkage and future association studies are warranted

Genetic Epidemiology of Attention Deficit Hyperactivity Disorder (ADHD Index) in Adults

Context: In contrast to the large number of studies in children, there is little information on the contribution of genetic factors to Attention Deficit Hyperactivity Disorder (ADHD) in adults. Objective: To estimate the heritability of ADHD in adults as assessed by the ADHD index scored from the CAARS (Conners’ Adult ADHD Rating Scales). Design: Phenotype data from over 12,000 adults (twins, siblings and parents) registered with the Netherlands Twin Register were analyzed using genetic structural equation modeling. Main outcome measures: Heritability estimates for ADHD from the twin-family study. Results: Heritability of ADHD in adults is estimated around 30 % in men and women. There is some evidence for assortative mating. All familial transmission is explained by genetic inheritance, there is no support for the hypothesis that cultural transmission from parents to offspring is important. Conclusion: Heritability for ADHD features in adults is present, but is substantially lower than it is in children

Genetics of schizophrenia: candidate genes and positional cloning analysis

Schizophrenia (SZ) is a multifactorial phenotype. Candidate gene approach and positional cloning are the primary methods for elucidating its etiology. We genotyped two TNF gene SNPs (-G308A, -G238A) and analyzed the haplotype structure in 24 Canadian families. Our results demonstrate that there is evidence for association (P=0.026) of a specific haplotype with SZ with a Trimhap test. Stratifying the 22 families with genome scan data by TNF promoter haplotypes followed by reanalysis of linkage to SZ, we identified few loci that exhibit a considerable increase in LOD/HLOD scores. A locus on chromosome 1q44 demonstrated a significant increase in LOD from 0.15 to 3.01. The synapsin 2 (Syn2) gene is implicated in synaptogenesis, neurotransmitter release, and the localization of nitric oxide synthase. 37 pedigrees of Northern European ancestry from the NIMH HGI collection were used in this study. Four microsatellites and twenty SNPs were genotyped. Linkage (FASTLINK) and association (TRANSMIT, PDTPHASE) were evaluated. A maximum HLOD of 1.93 was observed at D3S3434. Significant results were obtained for association with SZ using TRANSMIT (p=0.0000005) and PDTPHASE (p=0.014) using single marker analyses. Haplotype analysis provided a single haplotype that is significantly associated with SZ using TRANSMIT ([less than] 0.00000001) and PDTPHASE (p=0.02). The results of a linkage scan for SZ in the NIMH HGI Chinese family collection were reported by Faraone et al. with the largest NPL z score of 2.88 for D10S2327. We have reanalyzed the genome using the posterior probability of linkage (PPL). We split the sample into two subsets: those without any family members with affective diagnoses (SZ subgroup); and those with SZ, schizoaffective disorder, and bipolar disorder (HET subgroup). Genotypes were cleaned using PEDCHECK and SIMWALK. Sample specific genetic maps were constructed. SZ and HET groups were analyzed by four-point PPL analysis, and the results from each group were combined via pooling and sequential updating. The results confirmed the linkage peak on 10q22 with a PPL of 32.1% after updating. In addition we observed a peak of 30.5% over D3S1311 on 3q29 coming primarily from the HET group. Our results confirmed previous and yielded novel linkage findings in this family sample.Ph.D.Includes bibliographical references (p. 111-125)

Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia.

Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition

Heritability and genome-wide linkage scan of subjective happiness

Causes of individual differences in happiness, as assessed with the Subjective Happiness Scale, are investigated in a large of sample twins and siblings from the Netherlands Twin Register. Over 12,000 twins and siblings, average age 24.7 years (range 12 to 88), took part in the study. A genetic model with an age by sex design was fitted to the data with structural equation modeling in Mx. The heritability of happiness was estimated at 22% for males and 41% in females. No effect of age was observed. To identify the genomic regions contributing to this heritability, a genome-wide linkage study for happiness was conducted in sibling pairs. A subsample of 1157 offspring from 441 families was genotyped with an average of 371 micro-satellite markers per individual. Phenotype and genotype data were analyzed in MERLIN with multipoint variance component linkage analysis and age and sex as covariates. A linkage signal (logarithm of odds score 2.73, empirical p value 0.095) was obtained at the end of the long arm of chromosome 19 for marker D19S254 at 110 cM. A second suggestive linkage peak was found at the short arm of chromosome 1 (LOD of 2.37) at 153 cM, marker D1S534 (empirical p value of .209). These two regions of interest are not overlapping with the regions found for contrasting phenotypes (such as depression, which is negatively associated with happiness). Further linkage and future association studies are warranted

Lyso-Gb3 values for female and male Fabry patients compared to control.

<p>The horizontal mark indicated the median. It is noteworthy that lyso-Gb3 levels in males are ∼10 times higher than in females. Each data point represents one patient. Indicated in pink are patients with the mutation <i>p.S126G</i> (8f/4m), in blue <i>p.A143T</i> (10f/8m) and in green <i>p.D313Y</i> (33f/24m) to illustrate that most found non-pathogenic mutations belong to either one or the other patient cohort. Other exceptions are: <i>p.R118C</i>, <i>p.V316I</i>, <i>p.E418G</i> (one male patient each) and <i>p.A20P</i>, <i>p.D83N</i>, <i>p.I91T</i>, <i>p.S102L</i>, <i>p.R112C</i>, <i>p.R118C</i>, <i>p.D175E</i>, <i>p.G325S</i>, <i>p.A368T</i>, <i>p.T385A</i>, <i>p.W399*</i>, c.1208delT, <i>p.L415F</i>, (one female patient each) and <i>p.R252T</i> (4×), <i>p.N215S</i> (3×). About 180 healthy probands were tested with no Fabry gene variation and had values of 0.9 ng/ml (95^th percentile calculation).</p

Association of <i>in vitro</i> enzyme activity and clinical and computational parameters.

<p>Statistical association of enzyme activity and other parameters indicative for Fabry disease. The matrix confirms the high degree of translatability of <i>in vitro</i> data to the individual patients' biomarker phenotype. Lyso-Gb3-based classes of the mutants are fitting the enzyme activity classes.</p

Phenotype distribution of the ADHD index in men and women.

<p>ADHD index scores were transformed into T-scores separately by sex.</p

Number of participants for genetic analyses.

<p>Number of participants for genetic analyses.</p

Path diagram of phenotypic assortment model with genetic and cultural transmission from parents to offspring.

<p>Squares represent the phenotypes of a DZ twin pair (P_T1 and P_T2) with one extra sibling (P_Sib), and both parents (P_F and P_M). Latent factors are represented by circles and include A (additive genetic factor), D (dominance genetic factor), and E (non-shared environment). F represents vertical cultural transmission whereby the phenotype of the parents influences the environment of their offspring. Assortment of parents is modeled as a copath (i). Simultaneous genetic and cultural inheritance induces a correlation (s) between this environmental factor F and the genetic factor A. Path coefficients a, d and e represent the influence of latent factors on the phenotype. The variance due to vertical cultural transmission is represented by r and the variance of additive genetic factors by g.</p