Biomedical subjects

Nicholas G Martin

Publications and source records attributed to Nicholas G Martin.

At least 73 records · Page 4Linked to original sources

PubMed2005

Replicated linkage for eye color on 15q using comparative ratings of sibling pairs.

: The aim of the study was to perform a genetic linkage analysis for eye color, for comparative data. Similarity in eye color of mono- and dizygotic twins was rated by the twins' mother, their father and/or the twins themselves. For 4,748 twin pairs the similarity in eye color was available on a three point scale ("not at all alike"-"somewhat alike"-"completely alike"), absolute eye color on individuals was not assessed. The probability that twins were alike for eye color was calculated as a weighted average of the different responses of all respondents on several different time points. The mean probability of being alike for eye color was 0.98 for MZ twins (2,167 pairs), whereas the mean probability for DZ twins was 0.46 (2,537 pairs), suggesting very high heritability for eye color. For 294 DZ twin pairs genome-wide marker data were available. The probability of being alike for eye color was regressed on the average amount of IBD sharing. We found a peak LOD-score of 2.9 at chromosome 15q, overlapping with the region recently implicated for absolute ratings of eye color in Australian twins [Zhu, G., Evans, D. M., Duffy, D. L., Montgomery, G. W., Medland, S. E., Gillespie, N. A., Ewen, K. R., Jewell, M., Liew, Y. W., Hayward, N. K., Sturm, R. A., Trent, J. M., and Martin, N. G. (2004). Twin Res. 7:197-210] and containing the OCA2 gene, which is the major candidate gene for eye color [Sturm, R. A. Teasdale, R. D, and Box, N. F. (2001). Gene 277:49-62]. Our results demonstrate that comparative measures on relatives can be used in genetic linkage analysis.

Adolescent↗

PubMed2005

Genetic variation of individual alpha frequency (IAF) and alpha power in a large adolescent twin sample.

To further clarify the mode of genetic transmission on individual alpha frequency (IAF) and alpha power, the extent to which individual differences in these alpha indices are influenced by genetic factors were examined in a large sample of adolescent twins (237 MZ, 282 DZ pairs; aged 16). EEG was measured at rest (eyes closed) from the right occipital site, and a second EEG recording for 50 twin pairs obtained approximately 3 months after the initial collection, enabled an estimation of measurement error. Analyses confirmed a strong genetic influence on both IAF (h(2)=0.81) and alpha power (h(2)=0.82), and there was little support for non-additive genetic (dominance) variance. A small but significant negative correlation (-0.18) was found between IAF and alpha power, but genetic influences on IAF and alpha power were largely independent. All non-genetic variance was due to unreliability, with no significant variance attributed to unique environmental factors. Relationships between the alpha and IQ indices were also explored but were generally either non-significant or very low. The findings confirm the high heritability for both IAF and alpha power, they further suggest that the mode of genetic transmission is due to additive genetic factors, that genetic influences on the underlying neural mechanisms of alpha frequency and power are largely specific, and that individual differences in alpha activity are influenced little by developmental plasticity and individual experiences.

Adolescent↗

PubMed2005

Robust estimation of experimentwise P values applied to a genome scan of multiple asthma traits identifies a new region of significant linkage on chromosome 20q13.

Over 30 genomic regions show linkage to asthma traits. Six asthma genes have been cloned, but the putative loci in many linked regions have not been identified. To search for asthma susceptibility loci, we performed genomewide univariate linkage analyses of seven asthma traits, using 202 Australian families ascertained through a twin proband. House-dust mite sensitivity (Dpter) exceeded the empirical threshold for significant linkage at 102 cM on chromosome 20q13, near marker D20S173 (empirical pointwise P = .00001 and genomewide P = .005, both uncorrected for multiple-trait testing). Atopy, bronchial hyperresponsiveness (BHR), and forced expiratory volume in 1 s (FEV1) were also linked to this region. In addition, 16 regions were linked to at least one trait at the suggestive level, including 12q24, which has consistently shown linkage to asthma traits in other studies. Some regions were expected to be false-positives arising from multiple-trait testing. To address this, we developed a new approach to estimate genomewide significance that accounts for multiple-trait testing and for correlation between traits and that does not require a Bonferroni correction. With this approach, Dpter remained significantly linked to 20q13 (empirical genomewide P = .042), and airway obstruction remained linked to 12q24 at the suggestive level. Finally, we extended this method to show that the linkage of Dpter, atopy, BHR, FEV1, asthma, and airway obstruction to chromosome 20q13 is unlikely to be due to chance and may result from a quantitative trait locus in this region that affects several of these traits.

Adult↗

PubMed2005

Association between polymorphisms in the progesterone receptor gene and endometriosis.

The progesterone receptor (PR) is a candidate gene for the development of endometriosis, a complex disease with strong hormonal features, common in women of reproductive age. We typed the 306 base pair Alu insertion (AluIns) polymorphism in intron G of PR in 101 individuals, estimated linkage disequilibrium (LD) between five single-nucleotide polymorphisms (SNPs) across the PR locus in 980 Australian triads (endometriosis case and two parents) and used transmission disequilibrium testing (TDT) for association with endometriosis. The five SNPs showed strong pairwise LD, and the AluIns was highly correlated with proximal SNPs rs1042839 (delta2 = 0.877, D9 = 1.00, P < 0.0001) and rs500760 (delta2 = 0.438, D9 = 0.942, P < 0.0001). TDT showed weak evidence of allelic association between endometriosis and rs500760 (P = 0.027) but not in the expected direction. We identified a common susceptibility haplotype GGGCA across the five SNPs (P = 0.0167) in the whole sample, but likelihood ratio testing of haplotype transmission and non-transmission of the AluIns and flanking SNPs showed no significant pattern. Further, analysis of our results pooled with those from two previous studies suggested that neither the T2 allele of the AluIns nor the T1/T2 genotype was associated with endometriosis.

Adolescent↗

PubMed2005

Evaluation of multiple displacement amplification in a 5 cM STR genome-wide scan.

Multiple displacement amplification (MDA) has emerged as a promising new method of whole genome amplification (WGA) with the potential to generate virtually unlimited genome-equivalent DNA from only a small amount of seed DNA. To date, genome-wide high marker density assessments of MDA-DNA have focussed mainly upon suitability for single nucleotide polymorphism (SNP) genotyping applications. Suitability for short tandem repeat (STR) genotyping has not been investigated in great detail, despite their inherent instability during DNA replication, and the obvious challenge that this presents to WGA techniques. Here, we aimed to assess the applicability of MDA in STR genotyping by conducting a genome-wide scan of 768 STR markers for MDAs of 15 high quality genomic DNAs. We found that MDA genotyping call and accuracy rates were only marginally lower than for genomic DNA. Pooling of three replicate MDAs resulted in a small increase in both call rate and genotyping accuracy. We identified 34 STRs (4.4% of total markers) of which five essentially failed with MDA samples, and 29 of which showed elevated genotyping failures/discrepancies in the MDAs. We emphasise the importance of DNA and MDA quality checks, and the use of appropriate controls to identify problematic STR markers.

Female↗

PubMed2005

Genomewide significant linkage to migrainous headache on chromosome 5q21.

Familial typical migraine is a common, complex disorder that shows strong familial aggregation. Using latent-class analysis (LCA), we identified subgroups of people with migraine/severe headache in a community sample of 12,245 Australian twins (60% female), drawn from two cohorts of individuals aged 23-90 years who completed an interview based on International Headache Society criteria. We report results from genomewide linkage analyses involving 756 twin families containing a total of 790 independent sib pairs (130 affected concordant, 324 discordant, and 336 unaffected concordant for LCA-derived migraine). Quantitative-trait linkage analysis produced evidence of significant linkage on chromosome 5q21 and suggestive linkage on chromosomes 8, 10, and 13. In addition, we replicated previously reported typical-migraine susceptibility loci on chromosomes 6p12.2-p21.1 and 1q21-q23, the latter being within 3 cM of the rare autosomal dominant familial hemiplegic migraine gene (ATP1A2), a finding which potentially implicates ATP1A2 in familial typical migraine for the first time. Linkage analyses of individual migraine symptoms for our six most interesting chromosomes provide tantalizing hints of the phenotypic and genetic complexity of migraine. Specifically, the chromosome 1 locus is most associated with phonophobia; the chromosome 5 peak is predominantly associated with pulsating headache; the chromosome 6 locus is associated with activity-prohibiting headache and photophobia; the chromosome 8 locus is associated with nausea/vomiting and moderate/severe headache; the chromosome 10 peak is most associated with phonophobia and photophobia; and the chromosome 13 peak is completely due to association with photophobia. These results will prove to be invaluable in the design and analysis of future linkage and linkage disequilibrium studies of migraine.

Adult↗

PubMed2005

Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26.

Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families (931 from an Australian group and 245 from a U.K. group), each with at least two members--mainly affected sister pairs--with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 (MLS = 2.09). Minor peaks (with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.

Australia↗

PubMed2005

A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p.

Between 40% and 80% of the variation in human intelligence (IQ) is attributable to genetic factors. Except for many rare mutations resulting in severe cognitive dysfunction, attempts to identify these factors have not been successful. We report a genomewide linkage scan involving 634 sibling pairs designed to identify chromosomal regions that explain variation in IQ. Model-free multipoint linkage analysis revealed evidence of a significant quantitative-trait locus for performance IQ at 2q24.1-31.1 (LOD score 4.42), which overlaps the 2q21-33 region that has repeatedly shown linkage to autism. A second region revealed suggestive linkage for both full-scale and verbal IQs on 6p25.3-22.3 (LOD score 3.20 for full-scale IQ and 2.33 for verbal IQ), overlapping marginally with the 6p22.3-21.31 region implicated in reading disability and dyslexia.

Adolescent↗

PubMed2005

Erythrocyte aldehyde dehydrogenase activity: lack of association with alcohol use and dependence or alcohol reactions in Australian twins.

AIM: Aldehyde dehydrogenase 1 (ALDH1) has been advocated as a marker of alcohol intake. The absence or low levels of ALDH1 may be associated with alcohol-induced flushing or other reactions to alcohol in Europeans and therefore, with reduced alcohol use. This study tested whether variation in erythrocyte ALDH1 activity was associated with alcohol use, alcohol dependence or reactions to alcohol in unselected subjects of European descent, and whether variation in ALDH1 activity was subject to genetic influences. METHODS: ALDH activity was measured in erythrocytes from 677 men and women who had participated in a twin study of alcohol use and dependence. RESULTS: There were no significant effects of sex, alcohol consumption or alcohol dependence on ALDH activity. Subjects who reported reactions to alcohol did not have low activity. Women aged below 45 years had lower ALDH activity than men or older women. The heritability of ALDH activity was 56% (95% confidence interval = 42-67%). CONCLUSIONS: Previous reports that erythrocyte ALDH activity is low in alcoholics were not substantiated in this community-based sample. Associations with alcohol reactions were not found. ALDH activity varies widely between subjects, largely because of genetic factors.

Adult↗

PubMed2005

The genetic basis of academic achievement on the Queensland Core Skills Test and its shared genetic variance with IQ.

First, this study examined genetic and environmental sources of variation in performance on a standardised test of academic achievement, the Queensland Core Skills Test (QCST) (Queensland Studies Authority, 2003a). Second, it assessed the genetic correlation among the QCST score and Verbal and Performance IQ measures using the Multidimensional Aptitude Battery (MAB), [Jackson, D. N. (1984) Multidimensional Aptitude Battery manual. Port Huron, MI:Research Psychologist Press, Inc.]. Participants were 256 monozygotic twin pairs and 326 dizygotic twin pairs aged from 15 to 18 years (mean 17 years+/-0.4 [SD]) when achievement tested, and from 15 to 22 years (mean 16 years+/-0.4 [SD]) when IQ tested. Univariate analysis indicated a heritability for the QCST of 0.72. Adjustment to this estimate due to truncate selection (downward adjustment) and positive phenotypic assortative mating (upward adjustment) suggested a heritability of 0.76 The phenotypic (0.81) and genetic (0.91) correlations between the QCST and Verbal IQ (VIQ) were significantly stronger than the phenotypic (0.57) and genetic (0.64) correlations between the QCST and Performance IQ (PIQ). The findings suggest that individual variation in QCST performance is largely due to genetic factors and that common environmental effects may be substantially accounted for by phenotypic assortative mating. Covariance between academic achievement on the QCST and psychometric IQ (particularly VIQ) is to a large extent due to common genetic influences.

Adolescent↗

PubMed2005

Multivariate genetic analysis of chronic pelvic pain and associated phenotypes.

Chronic pelvic pain (CPP) is a common condition in women that is difficult to diagnose. Although heritability estimates have been published for some conditions potentially underlying pelvic pain, the heritability of CPP itself has never been investigated. Using data from 623 MZ and 377 DZ female twin pairs aged 29-50 from an Australian twin cohort, we found an increased CPP concordance among MZs compared to DZs, with tetrachoric correlations of 0.43 (95% CI: 0.26-0.58) and 0.11 (95% CI: -0.16-0.38), respectively. This corresponded to a heritability of 0.41 (95% CI: 0.25-0.56). Lack of correlations with environmental indicators suggested that violation of the equal environments assumption was not responsible for this effect. Multivariate Cholesky decomposition models incorporating CPP and significantly correlated phenotypes showed that the entire CPP heritability could be explained by genetic variance underlying endometriosis (38%), dysmenorrhoea (23%), fibroids (24%), and somatic distress (15%), the latter a possible indicator of increased nociception. CPP itself is unlikely to be a useful independent phenotype to conduct genetic aetiological studies; contributing conditions such as endometriosis and variation in nociception are likely to provide more useful phenotypes.

Adult↗

PubMed2005

Widespread evidence for non-additive genetic variation in Cloninger's and Eysenck's personality dimensions using a twin plus sibling design.

Studies using the classical twin design often conclude that most genetic variation underlying personality is additive in nature. However, studies analyzing only twins are very limited in their ability to detect non-additive genetic variation and are unable to detect sources of variation unique to twins, which can mask non-additive genetic variation. The current study assessed 9672 MZ and DZ twin individuals and 3241 of their siblings to investigate the environmental and genetic architecture underlying eight dimensions of personality: four from Eysenck's Personality Questionnaire and four from Cloninger's Temperament and Character Inventory. Broad-sense heritability estimates from best-fitting models were two to three times greater than the narrow-sense heritability estimates for Harm Avoidance, Novelty Seeking, Reward Dependence, Persistence, Extraversion, and Neuroticism. This genetic non-additivity could be due to dominance, additive-by-additive epistasis, or to additive genetic effects combined with higher-order epistasis. Environmental effects unique to twins were detected for both Lie and Psychoticism but accounted for little overall variation. Our results illustrate the increased sensitivity afforded by extending the classical twin design to include siblings, and may provide clues to the evolutionary origins of genetic variation underlying personality.

Australia↗

PubMed2005

Opposite effects of androgen receptor CAG repeat length on increased risk of left-handedness in males and females.

Prenatal exposure to testosterone has been hypothesised to effect lateralization by influencing cell death in the foetal brain. Testosterone binds to the X chromosome linked androgen receptor, which contains a polymorphic polyglutamine CAG repeat, the length of which is positively correlated with testosterone levels in males, and negatively correlated in females. To determine whether the length of the androgen receptor mediates the effects of testosterone on laterality, we examined the association between the number of CAG repeats in the androgen receptor gene and handedness for writing. Association was tested by adding regression terms for the length of the androgen receptor alleles to a multi-factorial-threshold model of liability to left-handedness. In females we found the risk of left-handedness was greater in those with a greater number of repeats (p=0.04), this finding was replicated in a second independent sample of female twins (p=0.014). The length of the androgen receptor explained 6% of the total variance and 24% of the genetic variance in females. In males the risk of left-handedness was greater in those with fewer repeats (p=0.02), with variation in receptor length explaining 10% of the total variance and 24% of the genetic variance. Thus, consistent with Witelson's theory of testosterone action, in all three samples the likelihood of left handedness increased in those individuals with variants of the androgen receptor associated with lower testosterone levels.

Adult↗

PubMed2005

An analysis of risk factors for cutaneous melanoma by anatomical site (Australia).

OBJECTIVE: Emerging evidence suggests that melanomas arising on the head and neck that are not lentigo maligna melanomas have different associations with phenotypic and environmental risk factors than those on the trunk and other sites. We sought to test this hypothesis in a population-based study in Queensland, Australia. METHODS: Risk factor data were collected from 2360 participants with incident cutaneous melanoma diagnosed 1982--1990, including 167 participants with lentigo maligna melanoma. For each risk factor, polytomous logistic regression analysis, using the trunk as a reference category, was used to estimate the odds ratio and 95% confidence interval for cutaneous melanomas by anatomical site. RESULTS: Participants with melanomas of the head and neck were significantly older than those with melanomas of the trunk (males 52.7 versus 49.7 years; females 47.8 versus 40.5 years). Compared with patients with truncal melanomas, those of the head and neck were less likely to have many nevi (OR 0.41, 95% CI 0.13--1.31), although this did not reach statistical significance. Among females, melanomas of the lower limb were negatively associated with a past history of non-melanoma skin cancer (OR 0.41, 95% CI 0.23-0.74). CONCLUSIONS: We have observed heterogeneity for melanoma risk by anatomical site, lending weight to the hypothesis that cutaneous melanomas may develop through multiple causal pathways.

Adult↗

PubMed2005

Perceptual speed does not cause intelligence, and intelligence does not cause perceptual speed.

There is ongoing debate whether the efficiency of local cognitive processes leads to global cognitive ability or whether global ability feeds the efficiency of basic processes. A prominent example is the well-replicated association between inspection time (IT), a measure of perceptual discrimination speed, and intelligence (IQ), where it is not known whether increased speed is a cause or consequence of high IQ. We investigated the direction of causation between IT and IQ in 2012 genetically related subjects from Australia and The Netherlands. Models in which the reliable variance of each observed variable was specified as a latent trait showed IT correlations of -0.44 and -0.33 with respective Performance and Verbal IQ; heritabilities were 57% (IT), 83% (PIQ) and 77% (VIQ). Directional causation models provided poor fits to the data, with covariation best explained by pleiotropic genes (influencing variation in both IT and IQ). This finding of a common genetic factor provides a better target for identifying genes involved in cognition than genes which are unique to specific traits.

Adolescent↗

PubMed2005

The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression.

BACKGROUND: Serotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression. METHOD: We typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype. RESULTS: There were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction. CONCLUSIONS: Regardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.

Aged↗

PubMed2005

A genetically informed study of marital instability and its association with offspring psychopathology.

Parental divorce is associated with a number of emotional and behavioral problems in young-adult offspring, but theoretical and empirical considerations suggest that the relation may be partially or fully accounted for by passive gene-environment correlation or environmental selection characteristics. The current study used the Children of Twins Design to explore whether shared environmental or genetic factors confound the relationship between parental marital instability and measures of psychopathology. Comparisons of the offspring of adult twins in Australia on 3 factors of abnormal behavior, including drug and alcohol, behavioral, and internalizing problems, suggest that environmental influences associated with divorce account for the higher rates of psychopathology. The results are consistent with a causal connection between marital instability and psychopathology in young-adult offspring.

Adult↗

PubMed2005

Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions.

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate.

Adolescent↗