The sociogenomics of sexual and reproductive behaviour
Melinda Mills University of Oxford & Nuffield College Completed Cohort Fertility, birth cohorts 1935-1972
Source: Human Fertility Database (https://www.humanfertility.org/cgi-bin/main.php), accessed April 3, 2018. Figure produced by Melinda. Average childlessness levels in Europe, women born 1900–1972
25 30 Italy & Spain European Average Nordic countries Austria, Germany, 25 20 Switzerland
Western 20 Europe 15
15
10
Central Europe 10 Shareof women childless (%) Eastern & south-eastern Europe Numberofcountries covered 5 5
0 0 1900 1905 1910 1915 1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970 Year of birth
Sobotka (2017) Women’s Mean Age First Birth, 1960-2016
32
Austria 30 Canada Czech Republic 28 Estonia Finland Hungary 26 Iceland Italy
24 Netherlands Norway Portugal
Women's Mean Age at First Birth First at Age Mean Women's 22 Spain Sweden Switzerland 20
USA
1974 2008 1960 1962 1964 1966 1968 1970 1972 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2010 2012 2014 Year Source: Human Fertility Database (https://www.humanfertility.org/cgi-bin/main.php), accessed April 3, 2018. Figure produced by Melinda.
Social behaviour (and some diseases) influenced by:
contraceptive laws; personality; partner reproductive span; childcare, & individual ovulation, sperm educational systems, characteristics production, etc. housing, marriage norms Sociogenomics: bridges 2 parallel approaches
Location of genetic variants (GWAS) Genetic Risk Fertility Predictive variable: polygenic score
Age at first birth Gene x Number of Environment children Infertility Contraception, norms & values, Menarche, Social factors, educational level, labour market menopause environment participation, role incompatibility, work-life, social networks, gender equity What do demographers know about sex and fertility? Sex and fertility demography = 28,313 citations
Top hits: • Sex ratio (17,050) • Divided by age and sex • Sex selection / sex (boy) preference • Same-sex couples Sexual intercourse, fertility and demography (4,489) …and contraceptive behaviour or use …and coitus interruptus …and abstinence …and HIV/AIDS …and preselection …and preference …and impact of female’s educational attainment …and breastfeeding …and at age first intercourse Sexual intercourse, fertility and demography (4,489) …and father absence …and sex roles …and violent conflict …and infant mortality …and cohabitation …and polygamy …and migration ...and seasonality of conception …and ‘premarital birth’ ‘Leading by losing: Sex and fertility on crack cocaine’ (1994) ‘Gall stones in a Danish population: fertility period, pregnancies and exogeneous female sex hormones’ (1988) Average age first sex (2005, 2007)
19,5 19,2 18,9 19 18,5 18,3 18,5 18,2 18,1 18,1 18 17,9 18 17,6 17,5 17,3 17,3 17 16,5 16,5 16,5 16,2 16,1 16 Average age first age sex first Average 15,6 15,5 15
Country
Durex Network Research Unit 2009, Face of Global Sex report, 2005 - 2009, SSL International plc, Cambridge, viewed 20th October, 2009,
Also link with reproductive window: age at menarche, voice breaking in boys, age at menopause Behavioural genetics Molecular genetics
% trait attributed to: Isolating genetic loci (SNPs, – Genes (heritability), single nucleotide – Shared family polymorphisms) environment, Examine biological structure & – Unshared environment function of genes (everything else + error) Heritability of fertility Around 25 to even 50%
Conclusions we can draw from twin studies
Large variation in heritability by: • Overall amount (25-50%) • Country • Birth cohort
Virtually no studies of men
Mills, M. & F. Tropf (2015). The biodemography of fertility: A review and future research frontiers Courtiol, Tropf & Mills (2016) When genes & environment disagree: Making Sense of Trends in Recent human evolution, Proceedings of the National Academy of Sciences, 113(28): 7693-95. uses measured SNPs to estimate genetic relatedness between unrelated individuals (Yang et al. 2010) 15% (AFB) and 10% (NEB) of variance explained by genetic variation So What?
Do they have a biological What are the genes? function? GWAS
• Genome-Wide Association Study • study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (breast cancer, age at first birth, educational attainment) • Data mining on SNPs • Mandatory independent QC & replication
Sample size AFB NEB Women 189,656 225,230 Men 48,408 103,909 Total 238,064 329,139 mean±SD 26.8±4.7 yrs 2.3±1.43 children
• 63 datasets from US, Canada, Northern & Western Europe (European ancestry)
• Data from scientific studies (medical, social science), insurance and commercial companies Age at first birth 10 significant loci 9 in both sexes 1 in women only
Number of children ever born 3 significant loci 2 in both sexes 1 in men only Identified causal function & role (e.g. gene expression analysis, gene methylation analysis, functional network or enrichment analysis, pathway analysis, regulatory analysis) • Sperm: spermatid differentiation (CREB3L4); spermatid maturation & acrosome reaction (HYAL3); spermatogenesis/testis (RBM5; CYHR1; GPT; RECQL4; PPP1R16A) • Fertility in female mice (EFNA5) • Hormones related to fertility (HCN1) • Ovum, oocyte, fallopian tube, prostate (e.g., MST1R; CRTC2) • Estrogen responsive gene, sexual maturation, development, (ESR1) • Metabolic endocrine abnormalities, FSH levels (GPT) • Endometriosis (GATAD2B, ESR1) • Polycystic ovary syndrome (DENND4B) Some genes have biological / epigenetic function
• Lead genetic loci on Chr 3 linked with: – methylation & expression of genes known to play a role in sperm function – Altering expression of genes RBM5/6 – linked to lower sperm count & quality Linked with human development
• LD Score regression • underlying human development, hormonal link • later AFB linked to later pubertal timing • Fertility shift Shift of reproductive window & longevity for those with particular genetic architecture
age first sex age menopause age menarche age first birth age death
probability
age 10 15 20 30 46 51 60 100 New study! • 4 Phenotypes: – number of children ever born, – childlessness, – age at first birth, – age at first sex • Pooled sample and by sex, birth year cohort • 1000G imputed genotype data • Analysis of X chromosome • Analysis plan pre-posted on OSF: https://osf.io/b4r4b/ • Analysis in 2 Centres
Larger sample combines 42 datasets
Age at Age at first Number Childless- first sex birth (AFB) of ness (CL) (AFS) children ever born (NEB)
Women 214,547 407,377 534,989 245,047 Men 182,791 124,008 301,525 205,035 Pooled 387,338 542,901 717,062 450,082 Many new genetic loci!
• 271 (Age first sex, AFS, previously 38), • 88 (Age first birth, AFB, 84 + 4 on the X Chromosome, previously 10), • 28 (Number of children ever born, NEB, previously 3) • 16 (CH, Childlessness) More & stronger genetic hits Polygenic scores
weighted average of individual genetic information Polygenic Score (PGS)
• R2 as a measure of goodness-of-fit
Out of sample prediction • ~5.5% of the variance for AFS, • ~3% for AFB • ~1.5% for NEB PGS getting close to standard demographic predictors!
10 9 8 7 6 5 4
PSEUDO R2 3 2 1 0 Age at Educational Labour force PGS Age PGS Age partnership attainment participation first sex first birth Pseudo R2 10 6,5 6 5,5 3 PGS prediction in multivariate models with standard predictors How well do PGS predict childlessness when social factors are included?
1.189** 1.304***
1.314*
0.612***
AFB PGS, 1.153*
1.094* Azoospermia 1.177* AFB PGS significant 1.127* significant
women men Reference groups: married before age 21, first job: clerk, LFP: job of 5+ years. Importance of social environment: time and space my mother me mother-in-law grandmother Age at first birth women, by birth cohort
Using HFD!
Tropf…M.C.Mills (2016) Nature Human Behavior
Increase explanation if you interact genetic component with birth cohort (C) and population (P) Increased genetic heritability by birth cohort
Mean AFB
SNP H2 G x E: Age life course effects
RENSKE VERWEIJ
Age: decreased biological ability to concieve by age
• PGS infertility stronger for women 35+ • PGS sperm defects stronger effects with age Genetic overlap fertility and related traits
David Brazel AFS & AFB Conclusion: Fertility is in the genes (and we know which ones)
• fertility has a genetic component • we offer you new variables to control for and test gene x environment relationships • sex is related to fertility • biological function of genetic loci (particularly men) • links to natural selection and evolution • Extend to non-European populations Conclusion: some critical thoughts 80-90% of genetic discovery European ancestry (N=3,639)
Mills & Rahal (2018) Communications Biology 72% respondents from 3 countries
Mills & Rahal (2018) Communications Biology www.sociogenome.org www.melindacmills.com Why the focus on European ancestry? • Analytical need for homogeneous cohorts (share geographic & socio-environmental factors) • Population stratification: subgroups have history of mixing & different ancestry • Subgroups differ in allele frequency & prevalence of a trait (e.g., type II diabetes in Native Americans) • Some SNPs more common in certain subgroups, thus risk for false positive
• Logistical, genetic, historical, funding, cultural reasons
Sexual dimorphism: genes contributing to female childlessness passed on via male lineage (and vice-versa for women)
We found different sets of genes for Example: female childlessness childlessness passed for men and on through male women lineage AFB PGS relevant birth cohorts 1933-1951 among men in HRS