Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Michailidou, Kyriaki,Beesley, Jonathan,Lindstrom, Sara,Canisius, Sander,Dennis, Joe,Lush, Michael J,Maranian, Mel J,Bolla, Manjeet K,Wang, Qin,Shah, Mitul,Perkins, Barbara J,Czene, Kamila,Eriksson, Mi Nature Publishing Group, a division of Macmillan P 2015 Nature genetics Vol.47 No.4

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10<SUP>−8</SUP>. Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

Stability of Wake-Sleep Cycles Requires Robust Degradation of the PERIOD Protein

D’Alessandro, Matthew,Beesley, Stephen,Kim, Jae Kyoung,Jones, Zachary,Chen, Rongmin,Wi, Julie,Kyle, Kathleen,Vera, Daniel,Pagano, Michele,Nowakowski, Richard,Lee, Choogon Elsevier 2017 Current biology Vol.27 No.22

<P><B>Summary</B></P> <P>Robustness in biology is the stability of phenotype under diverse genetic and/or environmental perturbations. The circadian clock has remarkable stability of period and phase that—unlike other biological oscillators—is maintained over a wide range of conditions. Here, we show that the high fidelity of the circadian system stems from robust degradation of the clock protein PERIOD. We show that PERIOD degradation is regulated by a balance between ubiquitination and deubiquitination, and that disruption of this balance can destabilize the clock. In mice with a loss-of-function mutation of the E3 ligase gene <I>β-Trcp2</I>, the balance of PERIOD degradation is perturbed and the clock becomes dramatically unstable, presenting a unique behavioral phenotype unlike other circadian mutant animal models. We believe that our data provide a molecular explanation for how circadian phases, such as wake-sleep onset times, can become unstable in humans, and we present a unique mouse model to study human circadian disorders with unstable circadian rhythm phases.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Nonlinear degradation of PER is required for the robustness of circadian rhythms </LI> <LI> PER degradation is regulated by a balance between ubiquitination and deubiquitination </LI> <LI> Disrupting this balance causes irregular wake-sleep cycles in mice </LI> </UL> </P>

Association analysis identifies 65 new breast cancer risk loci

Michailidou, Kyriaki,Lindströ,m, Sara,Dennis, Joe,Beesley, Jonathan,Hui, Shirley,Kar, Siddhartha,Lemaç,on, Audrey,Soucy, Penny,Glubb, Dylan,Rostamianfar, Asha,Bolla, Manjeet K.,Wang, Qin,Tyr Macmillan Publishers Limited, part of Springer Nat 2017 Nature Vol.551 No.7678

<P>Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry(1). We identified 65 new loci that are associated with overall breast cancer risk at P < 5 x 10(-8). The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.</P>

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Lin, Wei-Yu,Camp, Nicola J,Ghoussaini, Maya,Beesley, Jonathan,Michailidou, Kyriaki,Hopper, John L,Apicella, Carmel,Southey, Melissa C,Stone, Jennifer,Schmidt, Marjanka K,Broeks, Annegien,Van't Veer, L IRL Press 2015 Human molecular genetics Vol.24 No.1

<P>Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 ?? 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 ?? 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 ?? 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.</P>

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Milne, Roger L,Kuchenbaecker, Karoline B,Michailidou, Kyriaki,Beesley, Jonathan,Kar, Siddhartha,Lindströ,m, Sara,Hui, Shirley,Lemaç,on, Audrey,Soucy, Penny,Dennis, Joe,Jiang, Xia,Rostamianfa Nature Pub. Co 2017 Nature genetics Vol.49 No.12

<P>Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease(1). We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 x 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.</P>

Concurrent SHORT syndrome and 3q duplication syndrome

Boaz, Alexander M.,Grasso, Salvatore A.,DeRogatis, Michael J.,Beesley, Ellis N. Korean Society of Medical Genetics and Genomics 2019 대한의학유전학회지 Vol.16 No.1

SHORT syndrome is an extremely rare congenital condition due to a chromosomal mutation of the PIK3R1 gene found at 5q13.1. SHORT is a mnemonic representing six manifestations of the syndrome: (S) short stature, (H) hyperextensibility of joints and/or inguinal hernia, (O) ocular depression, (R) Rieger anomaly, and (T) teething delay. Other key aspects of this syndrome not found in the mnemonic include lipodystrophy, triangular face with dimpled chin (progeroid facies, commonly referred to as facial gestalt), hearing loss, vision loss, insulin resistance, and intrauterine growth restriction (IUGR). 3q duplication syndrome is rare syndrome that occurs due to a gain of function mutation found at 3q25.31-33 that presents with a wide array of manifestations including internal organ defects, genitourinary malformations, hand and foot deformities, and mental disability. We present a case of a 2 year and 3 month old male with SHORT syndrome and concurrent 3q duplication syndrome. The patient presented at birth with many of the common manifestations of SHORT syndrome such as bossing of frontal bone of skull, triangular shaped face, lipodystrophy, micrognathia, sunken eyes, and thin, wrinkled skin (progeroid appearance). Additionally, he presented with findings associated with 3q duplication syndrome such as cleft palate and cryptorchidism. Although there is no specific treatment for these conditions, pediatricians should focus on referring patients to various specialists in order to treat each individual manifestation.

Concurrent SHORT syndrome and 3q duplication syndrome

Alexander M. Boaz,Salvatore A. Grasso,Michael J. DeRogatis,Ellis N. Beesley 대한의학유전학회 2019 대한의학유전학회지 Vol.16 No.1

SHORT syndrome is an extremely rare congenital condition due to a chromosomal mutation of the PIK3R1 gene found at 5q13.1. SHORT is a mnemonic representing six manifestations of the syndrome: (S) short stature, (H) hyperextensibility of joints and/or inguinal hernia, (O) ocular depression, (R) Rieger anomaly, and (T) teething delay. Other key aspects of this syn-drome not found in the mnemonic include lipodystrophy, triangular face with dimpled chin (progeroid facies, commonly re-ferred to as facial gestalt), hearing loss, vision loss, insulin resistance, and intrauterine growth restriction (IUGR). 3q duplication syndrome is rare syndrome that occurs due to a gain of function mutation found at 3q25.31-33 that presents with a wide array of manifestations including internal organ defects, genitourinary malformations, hand and foot deformities, and mental dis-ability. We present a case of a 2 year and 3 month old male with SHORT syndrome and concurrent 3q duplication syndrome. The patient presented at birth with many of the common manifestations of SHORT syndrome such as bossing of frontal bone of skull, triangular shaped face, lipodystrophy, micrognathia, sunken eyes, and thin, wrinkled skin (progeroid appearance). Additionally, he presented with ἀndings associated with 3q duplication syndrome such as cleft palate and cryptorchidism. Al-though there is no speciἀc treatment for these conditions, pediatricians should focus on referring patients to various specialists in order to treat each individual manifestation.

Concurrent SHORT syndrome and 3q duplication syndrome

Alexander M,Boaz,Salvatore A,Grasso,Michael J,DeRogatis,Ellis N,Beesley 대한의학유전학회 2019 대한의학유전학회지 Vol.16 No.1

SHORT syndrome is an extremely rare congenital condition due to a chromosomal mutation of the PIK3R1 gene found at 5q13.1. SHORT is a mnemonic representing six manifestations of the syndrome: (S) short stature, (H) hyperextensibility of joints and/or inguinal hernia, (O) ocular depression, (R) Rieger anomaly, and (T) teething delay. Other key aspects of this syn-drome not found in the mnemonic include lipodystrophy, triangular face with dimpled chin (progeroid facies, commonly re-ferred to as facial gestalt), hearing loss, vision loss, insulin resistance, and intrauterine growth restriction (IUGR). 3q duplication syndrome is rare syndrome that occurs due to a gain of function mutation found at 3q25.31-33 that presents with a wide array of manifestations including internal organ defects, genitourinary malformations, hand and foot deformities, and mental dis-ability. We present a case of a 2 year and 3 month old male with SHORT syndrome and concurrent 3q duplication syndrome. The patient presented at birth with many of the common manifestations of SHORT syndrome such as bossing of frontal bone of skull, triangular shaped face, lipodystrophy, micrognathia, sunken eyes, and thin, wrinkled skin (progeroid appearance). Additionally, he presented with findings associated with 3q duplication syndrome such as cleft palate and cryptorchidism. Al-though there is no specific treatment for these conditions, pediatricians should focus on referring patients to various specialists in order to treat each individual manifestation.

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Dunning, Alison M,Michailidou, Kyriaki,Kuchenbaecker, Karoline B,Thompson, Deborah,French, Juliet D,Beesley, Jonathan,Healey, Catherine S,Kar, Siddhartha,Pooley, Karen A,Lopez-Knowles, Elena,Dicks, Ed Springer Science and Business Media LLC 2016 Nature genetics Vol.48 No.4

<P>We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.</P>