A study of Kibbutzim in Israel reveals risk factors for cardiometabolic traits and subtle population structure

Granot‐Hershkovitz, Einat; Karasik, David; Friedlander, Yechiel; Rodríguez-Murillo, Laura; Dorajoo, Rajkumar; Liu, Jing; Sewda, Anshuman; Peter, Inga; Carmi, Shai; Hochner, Hagit

doi:10.1038/s41431-018-0230-3

Cited by 14 publications

(21 citation statements)

References 60 publications

(87 reference statements)

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“…The KFS consists of 1033 participants from 150 extended families of Jewish ancestry, ranging from 2 to 55 individuals recruited during two visits in the 1990s from six Kibbutzim in Northern Israel, the majority (85%) from Ashkenazi origin [25]. Genome-wide genetic data were available for 901 of the participants.…”

Section: Datasetsmentioning

confidence: 99%

“…In JPS corresponding numbers were 398,491 variants and 872 individuals (658 complete trios, 192 parent-offspring duos and 22 offspring only). Imputation was done separately for each cohort using a combined reference panel of the 1000 genomes and The Ashkenazi Genome Consortium (n = 128) [25,32]. We considered imputed variants with MAF ≥ 1% and a strict imputation quality score ≥0.9 (hard calls).…”

Section: Genotyping and Quality Controlmentioning

confidence: 99%

“…We used the quantitative transmission disequilibrium test (QTDT) software [39] to test the genotype effect and the associations of maternally-and paternally-derived minor alleles using information from the extended families, adjusting for proband sex, age, study-specific covariate (i.e., visit in KFS and cohort in FHS), and first ten genotypic principal components (PCs). Principal component analysis was performed using PC-AiR [40], which is robust to known or cryptic relatedness as described elsewhere [25]. Specifically, the command "qtdt -at -ot" was used to test for POE (maternal effect = paternal effect), and "qtdt -at -om" and "qtdt -at -op" were used to test maternal and paternal effects, respectively (modified to adjust for the other parent's contribution).…”

Section: Kfs and Fhsmentioning

confidence: 99%

“…All models were adjusted for offspring sex and first 10 genotypic PCs calculated by PC-AiR [40], similarly to the KFS PCs calculations [25]. Offspring who reported using lipid-lowering medication (n = 13) or blood pressurelowering medication (n = 11) were excluded from the analyses.…”

Section: Jpsmentioning

confidence: 99%

“…To comprehensively examine POEs on a wide range of cardiometabolic traits we leveraged genome-wide array data in two unique Israeli family studies; the Kibbutzim Family Study (KFS) [25] comprising large families and the Jerusalem prenatal study (JPS) [26] comprising young adults and their parents. Focusing on imprinted genomic intervals spanning more than 50 M base pairs, we examined the associations of maternally-and paternally-derived minor alleles with 12 cardiometabolic traits.…”

Section: Introductionmentioning

confidence: 99%

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Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions

Granot‐Hershkovitz

Karasik

et al. 2020

Eur J Hum Genet

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Cardiometabolic traits pose a major global public health burden. Large-scale genome-wide association studies (GWAS) have identified multiple loci accounting for up to 30% of the genetic variance in complex traits such as cardiometabolic traits. However, the contribution of parent-of-origin effects (POEs) to complex traits has been largely ignored in GWAS. Familybased studies enable the assessment of POEs in genetic association analyses. We investigated POEs on a range of complex traits in 3 family-based studies. The discovery phase was carried out in large pedigrees from the Kibbutzim Family Study (n = 901 individuals) and in 872 parent-offspring trios from the Jerusalem Perinatal Study. Focusing on imprinted genomic regions, we examined parent-specific associations with 12 complex traits (i.e., body-size, blood pressure, lipids), mostly cardiometabolic risk traits. Forty five of the 11,967 SNPs initially found to have POE were evaluated for replication (p value < 1 × 10 −4 ) in Framingham Heart Study families (max n = 8000 individuals). Three common variants yielded evidence of POE in the meta-analysis. Two variants, located on chr6 in the HLA region, showed a paternal effect on height (rs1042136: β paternal = −0.023, p value = 1.5 × 10 −8 and rs1431403: β paternal = −0.011, p value = 5.4 × 10 −6 ). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (β maternal = −4.24, p value = 9.6 × 10 −6 ; β paternal = 1.29, p value = 0.23). These findings provide evidence for the utility of incorporating POEs into association studies of cardiometabolic traits, especially anthropometric traits. The study highlights the benefits of using family-based data for deciphering the genetic architecture of complex traits.

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Section: Datasetsmentioning

confidence: 99%

Section: Genotyping and Quality Controlmentioning

confidence: 99%

Section: Kfs and Fhsmentioning

confidence: 99%

Section: Jpsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions

Granot‐Hershkovitz

Karasik

et al. 2020

Eur J Hum Genet

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Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century

Waldman¹,

Backenroth²,

Harney³

et al. 2022

Cell

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Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes

et al. 2021

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Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of Body Mass Index (BMI) in three population-based cohorts from Northeast (Salvador), Southeast (Bambuí) and South (Pelotas) of the country. We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p= 2.76 e-06). This variant is very rare in Europeans but with frequencies of ~3% in West Africa, and has a strong female-specific effect (95%CI: 2.32-5.65 kg/m2 per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat-mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from São Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among morbidly obese women from Pelotas, São Paulo, and Bambuí. The effect size of rs114066381 is at least five-times the effect size of the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects, and for which we replicated associations in Pelotas. We demonstrate how, after a decade of GWAS mostly performed in European-ancestry populations, non-European and admixed populations are a source of new relevant phenotype-associated genetic variants.

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A study of Kibbutzim in Israel reveals risk factors for cardiometabolic traits and subtle population structure

Cited by 14 publications

References 60 publications

Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions

Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions

Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century

Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes

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