Genome-wide association analysis on monozygotic twin pairs offers a route to discovery of gene–environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high density lipoprotein (HDL) cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (p = 3.98 × 10−8). We followed up the association in further genotyped monozygotic twins (N = 1 261) which showed a moderate association for the variant (p = .002, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (p = 4.03 × 10−8).
twins; association; lipids; apolipoproteins; interaction
Genes encoding the opioid receptors (OPRM1, OPRD1, and
OPRK1) are obvious candidates for involvement in risk for
heroin dependence. Prior association studies commonly had samples of modest
size, included limited single nucleotide polymorphism (SNP) coverage of these
genes, and yielded inconsistent results. Participants for the current
investigation included 1459 heroin dependent cases ascertained from maintenance
clinics in New South Wales, Australia, 1495 unrelated individuals selected from
an Australian sample of twins and siblings as not meeting DSM-IV criteria for
lifetime alcohol or illicit drug dependence (non-dependent controls), and 531
controls ascertained from economically-disadvantaged neighborhoods in proximity
to the maintenance clinics. A total of 136 OPRM1, OPRD1, and
OPRK1 SNPs were genotyped in this sample. After controlling
for admixture with principal components analysis, our comparison of cases to
non-dependent controls found 4 OPRD1 SNPs in fairly high
linkage disequilibrium for which adjusted p values remained significant (e.g.,
rs2236857; OR 1.25; p=2.95 × 10−4) replicating a
previously reported association. A post-hoc analysis revealed that the two-SNP
(rs2236857 and rs581111) GA haplotype in OPRD1 is associated
with greater risk (OR 1.68; p=1.41 × 10−5). No
OPRM1 or OPRK1 SNPs reached more than
nominal significance. Comparisons of cases to neighborhood controls reached only
nominal significance. Our results replicate a prior report providing strong
evidence implicating OPRD1 SNPs and, in particular, the two SNP
(rs2236857 and rs581111) GA haplotype in liability for heroin dependence.
Support was not found for similar association involving either
OPRM1 or OPRK1 SNPs.
association study; heroin dependence; OPRD1; OPRK1; OPRM1
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.
The main genetic determinant of soluble IL-6R levels is the missense variant rs2228145, which maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ~20 ng/ml and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P = 0.0005), a proxy SNP for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P = 0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng/ml Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16 705 asthmatics and 30 809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P = 0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.
allergy; eQTL; expression; disease
The NTRK3 gene (also known as TRKC) encodes a high affinity receptor for the neurotrophin 3′-nucleotidase (NT3), which is implicated in oligodendrocyte and myelin development. We previously found that white matter integrity in young adults related to genetic variants in genes encoding neurotrophins and their receptors. This underscores the importance of neurotrophins for white matter development. NTRK3 variants are putative risk factors for schizophrenia, bipolar disorder, and obsessive-compulsive disorder hoarding, suggesting that some NTRK3 variants may affect the brain.
To test this, we scanned 392 healthy adult twins and their siblings (mean age, 23.6 ± 2.2 years; range: 20-29 years) with 105-gradient 4-Tesla diffusion tensor imaging (DTI). We identified 18 single nucleotide polymorphisms (SNPs) in the NTRK3 gene that have been associated with neuropsychiatric disorders. We used a multi-SNP model, adjusting for family relatedness, age, and sex, to relate these variants to voxelwise fractional anisotropy (FA) – a DTI measure of white matter integrity.
FA was optimally predicted (based on the highest false discovery rate critical p), by five SNPs (rs1017412, rs2114252, rs16941261, rs3784406, and rs7176429; overall FDR critical p = 0.028). Gene effects were widespread and included the corpus callosum genu and inferior longitudinal fasciculus - regions implicated in several neuropsychiatric disorders and previously associated with other neurotrophin-related genetic variants in an overlapping sample of subjects. NTRK3 genetic variants, and neurotrophins more generally, may influence white matter integrity in brain regions implicated in neuropsychiatric disorders.
Fractional anisotropy; diffusion tensor imaging; single nucleotide polymorphism; schizophrenia; obsessive compulsive disorder; bipolar disorder
Smoking is a major risk factor for several somatic diseases, and is also
emerging as a causal factor for neuropsychiatric disorders. Genome-wide
association (GWA) and candidate gene studies for smoking behavior and nicotine
dependence (ND) have disclosed too few predisposing variants to account for the
high estimated heritability. Prior large-scale GWA studies have had very limited
phenotypic definitions of relevance to smoking-related behavior, which has
likely impeded the discovery of genetic effects. We performed genome-wide
association analyses on 1114 adult twins ascertained for ever smoking from the
population-based Finnish Twin Cohort study. The availability of 17
smoking-related phenotypes allowed us to comprehensively portray the dimensions
of smoking behavior, clustered into the domains of smoking initiation, amount
smoked, and ND. Our results highlight a locus on 16p12.3, with several SNPs in
the vicinity of CLEC19A showing association
(P<1×10−6) with smoking
quantity. Interestingly, CLEC19A is located close to a
previously reported attention deficit hyperactivity disorder (ADHD) linkage
locus and an evident link between ADHD and smoking has been established.
Intriguing preliminary association
(P<1×10−5) was detected
between DSM-IV ND diagnosis and several SNPs in ERBB4, coding
for a Neuregulin receptor, on 2q33. The association between
ERBB4 and DSM-IV ND diagnosis was replicated in an
independent Australian sample. Interestingly, in the paper by Turner et al.,
significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed
following chronic nicotine exposure and withdrawal in mice. Turner et al. also
detected an association between NRG3 SNPs and smoking cessation
success in a clinical trial. ERBB4 has previously been
associated with schizophrenia; further, it is located within an established
schizophrenia linkage locus and within a linkage locus for a smoker phenotype
identified in this sample. As a conclusion, we disclose novel tentative evidence
for the involvement of ERBB4 in ND, suggesting the involvement
of the Neuregulin/ErbB signalling pathway in addictions and providing a
plausible link between the high co-morbidity of schizophrenia and ND.
genome-wide association analysis; nicotine dependence; smoking behavior; smoking quantity; schizophrenia; ADHD
Epistasis is the phenomenon whereby one polymorphism’s effect on a trait depends on other polymorphisms present in the genome. The extent to which epistasis influences complex traits1 and contributes to their variation2,3 is a fundamental question in evolution and human genetics. Though often demonstrated in artificial gene manipulation studies in model organisms4,5, and some examples have been reported in other species6, few examples exist for epistasis amongst natural polymorphisms in human traits7,8. Its absence from empirical findings may simply be due to low incidence in the genetic control of complex traits2,3, but an alternative view is that it has previously been too technically challenging to detect due to statistical and computational issues9. Here we show that, using advanced computation10 and a gene expression study design, many instances of epistasis are found between common single nucleotide polymorphisms (SNPs). In a cohort of 846 individuals with 7339 gene expression levels measured in peripheral blood, we found 501 significant pairwise interactions between common SNPs influencing the expression of 238 genes (p < 2.91 × 10−16). Replication of these interactions in two independent data sets11,12 showed both concordance of direction of epistatic effects (p = 5.56 ×10−31) and enrichment of interaction p-values, with 30 being significant at a conservative threshold of p < 0.05/501. Forty-four of the genetic interactions are located within 2Mb of regions of known physical chromosome interactions13 (p = 1.8 × 10−10). Epistatic networks of three SNPs or more influence the expression levels of 129 genes, whereby one cis-acting SNP is modulated by several trans-acting SNPs. For example MBNL1 is influenced by an additive effect at rs13069559 which itself is masked by trans-SNPs on 14 different chromosomes, with nearly identical genotype-phenotype (GP) maps for each cis-trans interaction. This study presents the first evidence for multiple instances of segregating common polymorphisms interacting to influence human traits.
Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.
telomere length; heritability; paternal age effect
Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and >2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10−10, and rs2769264, P = 2.63 × 10−20); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10−28 at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10−12; rs2120019, P = 1.55 × 10−18; and rs4826508, P = 1.40 × 10−12, respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10-9, two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
While the genetic contribution to the development of anorexia nervosa (AN) has long been recognized, there has been little progress relative to other psychiatric disorders in identifying specific susceptibility genes. Here we have carried out a GWAS on an unselected community sample of female twins surveyed for eating disorders.
We conducted genome wide association analyses in 2564 female twins for four different phenotypes derived from self-report data relating to lifetime presence of 15 types of disordered eating: anorexia nervosa spectrum, bulimia nervosa spectrum, purging via substances, and a binary measure of no disordered eating behaviors versus 3 or more. To complement the variant level results we also conducted gene-based association tests using VEGAS.
While no variants reached genome-wide significance at the level of p<10−8, six regions were suggestive (p<5×10−7). The current results implicate the following genes: CLEC5A; LOC136242, TSHZ1 and SYTL5 for the anorexia nervosa spectrum phenotype, NT5C1B for the bulimia nervosa spectrum phenotype, and ATP8A2 for the disordered eating behaviors phenotype.
As with other medical and psychiatric phenotypes, much larger samples and meta-analyses will ultimately be needed to identify genes and pathways contributing to predisposition to eating disorders.
To follow-up previous studies highlighting a possible role for cytochrome P450, family 2, subfamily C, 19 (CYP2C19) in susceptibility to endometriosis by searching for additional variants in the CYP2C19 gene that may be associated with the disease.
Cases = 2,271 women with surgically confirmed endometriosis; Controls = 939 women with self-report of no endometriosis and 1,770 unscreened population samples.
Sequencing of the CYP2C19 region and follow-up of 80 SNPs in two case-control samples.
Main outcome measure(s)
Allele frequency differences between cases and controls.
Sequencing of the CYP2C19 gene region resulted in the detection of a large number of known and novel SNPs. Genotyping of 80 polymorphic SNPs in 901 endometriosis cases and 939 controls resulted in study-wide significant association signals for SNPs in moderate or complete LD with rs4244285, a functional SNP in exon 5 that abrogates CYP2C19 function through the creation of an alternative splice site. Evidence of association was also detected for another functional SNP in the CYP2C19 promoter, rs12248560, highlighted in our previous study.
Functional variants in CYP2C19 may contribute to endometriosis susceptibility in both familial and sporadic cases.
Endometriosis; association; pooled sequencing; CYP2C19; rs12248560; rs4244285
While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic etiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with (>10,000 individuals). None of the genetic variants reached genome-wide significance. We also performed a gene-based association test, which also revealed no significant effects of individual genes. Finally, we estimated that only approximately 6.0% of the variation in cannabis initiation is due to common genetic variants. Future genetic studies using larger sample sizes and different methodologies (including sequencing) might provide more insight in the complex genetic etiology of cannabis use.
genetics; cannabis; heritability; association
Genome-wide association studies show strong evidence of association with endometriosis for markers on chromosome 1p36 spanning the potential candidate genes WNT4, CDC42 and LINC00339. WNT4 is involved in development of the uterus, and the expression of CDC42 and LINC00339 are altered in women with endometriosis. We conducted fine mapping to examine the role of coding variants in WNT4 and CDC42 and determine the key SNPs with strongest evidence of association in this region. We identified rare coding variants in WNT4 and CDC42 present only in endometriosis cases. The frequencies were low and cannot account for the common signal associated with increased risk of endometriosis. Genotypes for five common SNPs in the region of chromosome 1p36 show stronger association signals when compared with rs7521902 reported in published genome scans. Of these, three SNPs rs12404660, rs3820282, and rs55938609 were located in DNA sequences with potential functional roles including overlap with transcription factor binding sites for FOXA1, FOXA2, ESR1, and ESR2. Functional studies will be required to identify the gene or genes implicated in endometriosis risk.
Endometriosis; WNT4; CDC42; chromosome 1p36; rare variants; common variants
Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10−06, KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene.
personality; KCNJ1; NEO; linkage; GSMA
Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)2), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970–2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9–17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
adiposity; body mass index; genetic association studies; menarche; obesity; waist circumference; waist:hip ratio; women's health
The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.
Large genetic association studies have revealed many genetic factors influencing common traits, such as body mass index (BMI). These studies assume that the effect of genetic variants is the same regardless of whether they are inherited from the mother or the father. In our study, we have developed a new approach that allows us to investigate variants whose impact depends on their parental origin (parent-of-origin effects), in unrelated samples when the parental origin cannot be inferred. This is feasible because at genetic markers at which such effects occur there is increased variability of the trait among individuals who inherited different genetic codes from their mother and their father compared to individuals who inherited the same genetic code from both parents. We applied this methodology to discover genetic markers with parent-of-origin effects (POEs) on BMI. This resulted in six candidate markers showing strong POE association. We then attempted to replicate the POE effects of these markers in family studies (where one can infer the parental origin of the inherited variants). Two of our candidates showed significant association in the family studies, the paternal and maternal effects of these markers were in the opposite direction.
The SNP-SNP interactome has rarely been explored in the context of neuroimaging genetics mainly due to the complexity of conducting ∼1011 pairwise statistical tests. However, recent advances in machine learning, specifically the iterative sure independence screening (SIS) method, have enabled the analysis of datasets where the number of predictors is much larger than the number of observations. Using an implementation of the SIS algorithm (called EPISIS), we used exhaustive search of the genome-wide, SNP-SNP interactome to identify and prioritize SNPs for interaction analysis. We identified a significant SNP pair, rs1345203 and rs1213205, associated with temporal lobe volume. We further examined the full-brain, voxelwise effects of the interaction in the ADNI dataset and separately in an independent dataset of healthy twins (QTIM). We found that each additional loading in the epistatic effect was associated with ∼5% greater brain regional brain volume (a protective effect) in both the ADNI and QTIM samples.
epistasis; interaction; genome; sure independence; tensor-based morphometry
Several aspects of sleep behaviour such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of 6 sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317K, 370K and 610K arrays and the common Single Nucleotide Polymorphisms between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the 3rd intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (p = 1.3 × 10−6). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (p = 0.73). We have identified several other associations that await replication in an independent sample. Our study had good power to detect common single nucleotide polymorphisms that explain more than 2% of the phenotypic variance in self-report sleep phenotypes at a genome-wide significant level. No such variants were detected.
insomnia; genetics; mood; sleep; circadian
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10−8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
Partner and localizer of BRCA2 (PALB2) interacts with BRCA2 to enable double strand break repair through homologous recombination. Similar to BRCA2, germline mutations in PALB2 have been shown to predispose to Fanconi anaemia as well as pancreatic and breast cancer. The PALB2/BRCA2 protein interaction, as well as the increased melanoma risk observed in families harbouring BRCA2 mutations, makes PALB2 a candidate for melanoma susceptibility. In order to assess PALB2 as a melanoma predisposition gene, we sequenced the entire protein-coding sequence of PALB2 in probands from 182 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, and BAP1. In addition, we interrogated whole-genome and exome data from another 19 kindreds with a strong family history of melanoma for deleterious mutations in PALB2. Here we report a rare known deleterious PALB2 mutation (rs118203998) causing a premature truncation of the protein (p.Y1183X) in an individual who had developed four different cancer types, including melanoma. Three other family members affected with melanoma did not carry the variant. Overall our data do not support a case for PALB2 being associated with melanoma predisposition.
Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single-nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders.
neuroimaging; genetics; neurodegeneration; drug addiction; opiates
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
Deficits in lentiform nucleus volume and morphometry are implicated in a number of genetically influenced disorders, including Parkinson’s disease, schizophrenia, and ADHD. Here we performed genome-wide searches to discover common genetic variants associated with differences in lentiform nucleus volume in human populations. We assessed structural MRI scans of the brain in two large genotyped samples: the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N=706) and the Queensland Twin Imaging Study (QTIM; N=639). Statistics of association from each cohort were combined meta-analytically using a fixed-effects model to boost power and to reduce the prevalence of false positive findings. We identified a number of associations in and around the flavin-containing monooxygenase (FMO) gene cluster. The most highly associated SNP, rs1795240, was located in the FMO3 gene; after meta-analysis, it showed genome-wide significant evidence of association with lentiform nucleus volume (PMA=4.79×10−8). This commonly-carried genetic variant accounted for 2.68 % and 0.84 % of the trait variability in the ADNI and QTIM samples, respectively, even though the QTIM sample was on average 50 years younger. Pathway enrichment analysis revealed significant contributions of this gene to the cytochrome P450 pathway, which is involved in metabolizing numerous therapeutic drugs for pain, seizures, mania, depression, anxiety, and psychosis. The genetic variants we identified provide replicated, genome-wide significant evidence for the FMO gene cluster’s involvement in lentiform nucleus volume differences in human populations.
Basal ganglia; Genome-wide association study (GWAS); MRI; Replication; Morphometry; Drug metabolism