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

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1900 1905 1910 1915 1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970

Nu

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cove

red

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ildle

ss (

%)

Year of birth

European AverageAustria, Germany, Switzerland

Eastern & south-eastern Europe

Central Europe

Western Europe

Italy & Spain

Nordic countries

Sobotka (2017)

Women’s Mean Age First Birth, 1960-2016

Source: Human Fertility Database (https://www.humanfertility.org/cgi-bin/main.php), accessed April

3, 2018. Figure produced by Melinda.

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men

's M

ean

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e at

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irth

Year

Austria

Canada

Czech Republic

Estonia

Finland

Hungary

Iceland

Italy

Netherlands

Norway

Portugal

Spain

Sweden

Switzerland

USA

Social behaviour (and some diseases)influenced by:

reproductive span;

ovulation, sperm

production, etc.

personality; partner

& individual

characteristics

contraceptive laws;

childcare,

educational systems,

housing, marriage

norms

Contraception, norms & values, educational level, labour market participation, role incompatibility, work-life, social networks, gender equity

Social factors, environment

Age at first birth

Number of children

Infertility

Menarche, menopause

Genetic RiskLocation of genetic variants (GWAS)

Predictive variable: polygenic score

Gene x Environment

Fertility

Sociogenomics: bridges 2 parallel approaches

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)

19,218,9

18,518,3 18,2 18,1 18,1 18 17,9

17,617,3 17,3

16,5 16,516,2 16,1

15,6

15

15,5

16

16,5

17

17,5

18

18,5

19

19,5

Av

era

ge

ag

e fi

rst

sex

Country

Durex Network Research Unit 2009, Face of Global Sex report, 2005 - 2009, SSL International plc, Cambridge, viewed 20th October, 2009, <http://www.durexnetwork.org/en-GB/research>.

Harris Interactive 2006, The Durex Sexual Wellbeing Global Survey, 2006, SSL International plc, Cambridge, viewed 20th October, 2009, <http://www.durex.com/en-US/SexualWellbeingSurvey>.

Sexual behavior & fertility

• AFS: Age at first sexual intercourse

• AFB: Age at first birth

• NEB: Number of children ever born

• CL: Childlessness

Also link with reproductive window:

age at menarche, voice breaking in boys, age at menopause

Behavioural genetics

% trait attributed to:

– Genes (heritability),

– Shared family

environment,

– Unshared environment

(everything else + error)

Molecular genetics

Isolating genetic loci (SNPs,

single nucleotide

polymorphisms)

Examine biological structure &

function of genes

Heritability of fertilityAround 25 to even 50%

Mills, M. & F. Tropf (2015). The biodemography of fertility: A review and future research frontiers

Conclusions we can draw from twin studies

Large variation in heritability by:• Overall amount (25-50%)• Country• Birth cohort

Virtually no studies of men

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?

What are the genes?Do they have a biological

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

Totalmean±SD

238,06426.8±4.7 yrs

329,1392.3±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

probability

100age

10 20 51 60463015

age menarcheage first sex

age first birthage menopause

age death

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

first sex

(AFS)

Age at first

birth (AFB)

Number

of

children

ever born

(NEB)

Childless-

ness (CL)

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!

Age at

partnership

Educational

attainment

Labour force

participation

PGS Age

first sex

PGS Age

first birth

Pseudo R2 10 6,5 6 5,5 3

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EU

DO

R2

PGS prediction in multivariate models with standard

predictors

How well do PGS predict childlessness when social factors are included?

women men

AFB PGS

significant

AFB PGS,

Azoospermia

significant

Reference groups: married before age 21, first job: clerk, LFP: job of 5+ years.

1.094*

1.314*

0.612***

1.304***

1.189**

1.153*

1.127*1.177*

grandmothermother-in-law

Importance of social environment: time and space

my mother me

Tropf…M.C.Mills (2016) Nature Human Behavior

Age at first birth women,by birth cohort

Using HFD!

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

Age: decreasedbiological ability toconcieve by age

• PGS infertility strongerfor women 35+

• PGS sperm defects stronger effects withage

RENSKE

VERWEIJ

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)

Example: female childlessness passed on through male lineage

We found different sets of genes for childlessness for men and women

AFB PGS relevant birth cohorts 1933-1951 among men in HRS